Proteotoxicity and Neurodegenerative Diseases
Abstract
1. Introduction
2. Proteotoxicity in Huntington Disease
2.1. Structure of the Huntingtin Protein
2.2. Physiological Role of the Huntingtin Protein
2.3. Pathological Mechanisms of Huntingtin Aggregation
2.4. Therapeutic Insights
3. Proteotoxicity in Amyotrophic Lateral Sclerosis
3.1. Structure of the TDP-43 Protein
3.2. Physiological Functions of TDP-43
3.3. Pathological Mechanisms of TDP-43 Aggregation
3.4. Prion-like Behavior of TDP-43 Aggregates
3.5. Other Proteins Involved in Amyotrophic Lateral Sclerosis
3.6. Therapeutic Insights
4. Proteotoxicity in Parkinson’s Disease
4.1. Structure and Physiological Function of α-Synuclein
4.2. Pathologic Mechanisms of α-Synuclein Aggregation
4.3. Therapeutic Insights
5. Proteotoxicity in Alzheimer’s Disease
5.1. Structure of the Amyloid-β Peptide
5.2. Physiological Role of the Amyloid Precursor Protein (APP) and Aβ Peptide
5.3. Pathological Mechanisms of β-Amyloid Peptide Aggregation
5.4. Tau and Phosphorylated Tau
5.5. Therapeutic Insights
6. Concluding Remarks and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
PD | Parkinson’s disease |
ALS | Amyotrophic lateral sclerosis |
FTD | Frontotemporal dementia |
HD | Huntington’s disease |
PQC | Protein quality control |
UPS | Ubiquitin-proteasome system |
polyQ | Polyglutamine |
BDNF | Brain-derived neurotrophic factor |
AAV | Adeno-associate virus |
ASOs. | Antisense oligonucleotides |
SOD1 | Superoxide Dismutase 1 |
FUS | Fused in Sarcoma |
TBK-1 | TANK-binding kinase 1 |
hnRNP | Ribonucleoprotein family |
TPD-43 | TAR DNA-binding protein 43 |
NTD | N-Terminal Domain |
RRMs | RNA Recognition Motifs |
NES | Nuclear Export Signal |
NLS | Nuclear Localization Signal |
CTD | C-Terminal Domain |
CTF | C-terminal fragments |
RBP | RNA binding protein |
ROS | Reactive oxygen species |
Q | Glutamines |
NLS | C-terminal nuclear localization signal |
CTF | C-terminal fragments |
RBP | RNA binding protein |
KD | Kinase domain |
ULD | Ubiquitin-like domain |
CCD1 and CCD2 | Two coiled-coil domains |
AIM4 | Acridine-imidazole derivative |
LB | Lewy bodies |
LN | Lewy neurites |
ER | Endoplasmic reticulum |
ALP | Autophagy lysosomal pathway |
AB | Amyloid-beta |
APP | Amyloid precursor protein |
PSEN1 | Presenilin 1 |
PSEN2 | Presenilin 2 |
APP | Amyloid precursor protein |
sAPP | Secreted APP |
GABABR1a | Gamma-aminobutyric acid type B receptor subunit 1a |
LTP | Promote long-term potentiation |
NGF | Nerve growth factor |
MDR | Microtubule-binding domain |
References
- Hou, Y.; Dan, X.; Babbar, M.; Wei, Y.; Hasselbalch, S.G.; Croteau, D.L.; Bohr, V.A. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 2019, 15, 565–581. [Google Scholar] [CrossRef] [PubMed]
- Sweeney, P.; Park, H.; Baumann, M.; Dunlop, J.; Frydman, J.; Kopito, R.; McCampbell, A.; Leblanc, G.; Venkateswaran, A.; Nurmi, A.; et al. Protein misfolding in neurodegenerative diseases: Implications and strategies. Transl. Neurodegener. 2017, 6, 6. [Google Scholar] [CrossRef] [PubMed]
- Kumar, V.; Sami, N.; Kashav, T.; Islam, A.; Ahmad, F.; Hassan, M.I. Protein aggregation and neurodegenerative diseases: From theory to therapy. Eur. J. Med. Chem. 2016, 124, 1105–1120. [Google Scholar] [CrossRef] [PubMed]
- Sameni, S.; Malacrida, L.; Tan, Z.; Digman, M.A. Alteration in Fluidity of Cell Plasma Membrane in Huntington Disease Revealed by Spectral Phasor Analysis. Sci. Rep. 2018, 8, 734. [Google Scholar] [CrossRef] [PubMed]
- Bae, B.-I.; Xu, H.; Igarashi, S.; Fujimuro, M.; Agrawal, N.; Taya, Y.; Hayward, S.D.; Moran, T.H.; Montell, C.; Ross, C.A.; et al. p53 mediates cellular dysfunction and behavioral abnormalities in Huntington’s disease. Neuron 2005, 47, 29–41. [Google Scholar] [CrossRef] [PubMed]
- Zuccato, C.; Marullo, M.; Vitali, B.; Tarditi, A.; Mariotti, C.; Valenza, M.; Lahiri, N.; Wild, E.J.; Sassone, J.; Ciammola, A.; et al. Brain-derived neurotrophic factor in patients with Huntington’s disease. PLoS ONE 2011, 6, e22966. [Google Scholar] [CrossRef] [PubMed]
- Ravikumar, B.; Duden, R.; Rubinsztein, D.C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 2002, 11, 1107–1117. [Google Scholar] [CrossRef]
- Holmberg, C.I.; Staniszewski, K.E.; Mensah, K.N.; Matouschek, A.; Morimoto, R.I. Inefficient degradation of truncated polyglutamine proteins by the proteasome. EMBO J. 2004, 23, 4307–4318. [Google Scholar] [CrossRef]
- Kuhl, D.E.; Metter, E.J.; Riege, W.H.; Markham, C.H. Patterns of cerebral glucose utilization in Parkinson’s disease and Huntington’s disease. Ann. Neurol. 1984, 15, S119–S125. [Google Scholar] [CrossRef]
- Kuwert, T.; Lange, H.W.; Langen, K.J.; Herzog, H.; Aulich, A.; Feinendegen, L.E. Cortical and subcortical glucose consumption measured by PET in patients with Huntington’s disease. Brain 1990, 113, 1405–1423. [Google Scholar] [CrossRef]
- Crotti, A.; Benner, C.; Kerman, B.E.; Gosselin, D.; Lagier-Tourenne, C.; Zuccato, C.; Cattaneo, E.; Gage, F.H.; Cleveland, D.W.; Glass, C.K. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat. Neurosci. 2014, 17, 513–521. [Google Scholar] [CrossRef] [PubMed]
- Ide, K.; Nukina, N.; Masuda, N.; Goto, J.; Kanazawa, I. Abnormal gene product identified in Huntington’s disease lymphocytes and brain. Biochem. Biophys. Res. Commun. 1995, 209, 1119–1125. [Google Scholar] [CrossRef] [PubMed]
- Wellington, C.L.; Ellerby, L.M.; Gutekunst, C.-A.; Rogers, D.; Warby, S.; Graham, R.K.; Loubser, O.; Van Raamsdonk, J.; Singaraja, R.; Yang, Y.-Z.; et al. Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington’s disease. J. Neurosci. 2002, 22, 7862–7872. [Google Scholar] [CrossRef] [PubMed]
- Highley, J.R.; Kirby, J.; Jansweijer, J.A.; Webb, P.S.; Hewamadduma, C.A.; Heath, P.R.; Higginbottom, A.; Raman, R.; Ferraiuolo, L.; Cooper-Knock, J.; et al. Loss of nuclear TDP-43 in amyotrophic lateral sclerosis (ALS) causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurones. Neuropathol. Appl. Neurobiol. 2014, 40, 670–685. [Google Scholar] [CrossRef] [PubMed]
- Arnold, E.S.; Ling, S.-C.; Huelga, S.C.; Lagier-Tourenne, C.; Polymenidou, M.; Ditsworth, D.; Kordasiewicz, H.B.; McAlonis-Downes, M.; Platoshyn, O.; Parone, P.A.; et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc. Natl. Acad. Sci. USA 2013, 110, E736–E745. [Google Scholar] [CrossRef]
- Russo, A.; Scardigli, R.; La Regina, F.; Murray, M.E.; Romano, N.; Dickson, D.W.; Wolozin, B.; Cattaneo, A.; Ceci, M. Increased cytoplasmic TDP-43 reduces global protein synthesis by interacting with RACK1 on polyribosomes. Hum. Mol. Genet. 2017, 26, 1407–1418. [Google Scholar] [CrossRef]
- Wang, W.; Li, L.; Lin, W.-L.; Dickson, D.W.; Petrucelli, L.; Zhang, T.; Wang, X. The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. Hum. Mol. Genet. 2013, 22, 4706–4719. [Google Scholar] [CrossRef]
- Stribl, C.; Samara, A.; Trümbach, D.; Peis, R.; Neumann, M.; Fuchs, H.; Gailus-Durner, V.; Hrabě de Angelis, M.; Rathkolb, B.; Wolf, E.; et al. Mitochondrial dysfunction and decrease in body weight of a transgenic knock-in mouse model for TDP-43. J. Biol. Chem. 2014, 289, 10769–10784. [Google Scholar] [CrossRef]
- Xia, Q.; Wang, H.; Hao, Z.; Fu, C.; Hu, Q.; Gao, F.; Ren, H.; Chen, D.; Han, J.; Ying, Z.; et al. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016, 35, 121–142. [Google Scholar] [CrossRef]
- Araki, W.; Minegishi, S.; Motoki, K.; Kume, H.; Hohjoh, H.; Araki, Y.M.; Tamaoka, A. Disease-associated mutations of TDP-43 promote turnover of the protein through the proteasomal pathway. Mol. Neurobiol. 2014, 50, 1049–1058. [Google Scholar] [CrossRef]
- Barmada, S.J.; Serio, A.; Arjun, A.; Bilican, B.; Daub, A.; Ando, D.M.; Tsvetkov, A.; Pleiss, M.; Li, X.; Peisach, D.; et al. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat. Chem. Biol. 2014, 10, 677–685. [Google Scholar] [CrossRef] [PubMed]
- Liu, G.; Coyne, A.N.; Pei, F.; Vaughan, S.; Chaung, M.; Zarnescu, D.C.; Buchan, J.R. Endocytosis regulates TDP-43 toxicity and turnover. Nat. Commun. 2017, 8, 2092. [Google Scholar] [CrossRef] [PubMed]
- Schwenk, B.M.; Hartmann, H.; Serdaroglu, A.; Schludi, M.H.; Hornburg, D.; Meissner, F.; Orozco, D.; Colombo, A.; Tahirovic, S.; Michaelsen, M.; et al. TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons. EMBO J. 2016, 35, 2350–2370. [Google Scholar] [CrossRef] [PubMed]
- Dang, T.N.T.; Lim, N.K.H.; Grubman, A.; Li, Q.-X.; Volitakis, I.; White, A.R.; Crouch, P.J. Increased metal content in the TDP-43(A315T) transgenic mouse model of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Front. Aging Neurosci. 2014, 6, 15. [Google Scholar] [CrossRef] [PubMed]
- Caragounis, A.; Price, K.A.; Soon, C.P.W.; Filiz, G.; Masters, C.L.; Li, Q.-X.; Crouch, P.J.; White, A.R. Zinc induces depletion and aggregation of endogenous TDP-43. Free Radic. Biol. Med. 2010, 48, 1152–1161. [Google Scholar] [CrossRef] [PubMed]
- Berson, A.; Sartoris, A.; Nativio, R.; Van Deerlin, V.; Toledo, J.B.; Porta, S.; Liu, S.; Chung, C.-Y.; Garcia, B.A.; Lee, V.M.-Y.; et al. TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. Curr. Biol. 2017, 27, 3579–3590.e6. [Google Scholar] [CrossRef]
- Sun, Z.; Diaz, Z.; Fang, X.; Hart, M.P.; Chesi, A.; Shorter, J.; Gitler, A.D. Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biol. 2011, 9, e1000614. [Google Scholar] [CrossRef]
- Marrone, L.; Drexler, H.C.A.; Wang, J.; Tripathi, P.; Distler, T.; Heisterkamp, P.; Anderson, E.N.; Kour, S.; Moraiti, A.; Maharana, S.; et al. FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy. Acta Neuropathol. 2019, 138, 67–84. [Google Scholar] [CrossRef]
- Lin, C.L.; Bristol, L.A.; Jin, L.; Dykes-Hoberg, M.; Crawford, T.; Clawson, L.; Rothstein, J.D. Aberrant RNA processing in a neurodegenerative disease: The cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 1998, 20, 589–602. [Google Scholar] [CrossRef]
- Trotti, D.; Rolfs, A.; Danbolt, N.C.; Brown, R.H., Jr.; Hediger, M.A. SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat. Neurosci. 1999, 2, 427–433. [Google Scholar] [CrossRef]
- Chung, M.J.; Suh, Y.-L. Ultrastructural changes of mitochondria in the skeletal muscle of patients with amyotrophic lateral sclerosis. Ultrastruct. Pathol. 2002, 26, 3–7. [Google Scholar] [CrossRef] [PubMed]
- Echaniz-Laguna, A.; Zoll, J.; Ribera, F.; Tranchant, C.; Warter, J.-M.; Lonsdorfer, J.; Lampert, E. Mitochondrial respiratory chain function in skeletal muscle of ALS patients. Ann. Neurol. 2002, 52, 623–627. [Google Scholar] [CrossRef] [PubMed]
- Sasaki, S.; Iwata, M. Mitochondrial alterations in the spinal cord of patients with sporadic amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 2007, 66, 10–16. [Google Scholar] [CrossRef] [PubMed]
- Kieran, D.; Hafezparast, M.; Bohnert, S.; Dick, J.R.T.; Martin, J.; Schiavo, G.; Fisher, E.M.C.; Greensmith, L. A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice. J. Cell Biol. 2005, 169, 561–567. [Google Scholar] [CrossRef] [PubMed]
- Williamson, T.L.; Cleveland, D.W. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat. Neurosci. 1999, 2, 50–56. [Google Scholar] [CrossRef]
- Bilsland, L.G.; Sahai, E.; Kelly, G.; Golding, M.; Greensmith, L.; Schiavo, G. Deficits in axonal transport precede ALS symptoms in vivo. Proc. Natl. Acad. Sci. USA 2010, 107, 20523–20528. [Google Scholar] [CrossRef] [PubMed]
- Simpson, E.P.; Henry, Y.K.; Henkel, J.S.; Smith, R.G.; Appel, S.H. Increased lipid peroxidation in sera of ALS patients: A potential biomarker of disease burden. Neurology 2004, 62, 1758–1765. [Google Scholar] [CrossRef]
- Chang, Y.; Kong, Q.; Shan, X.; Tian, G.; Ilieva, H.; Cleveland, D.W.; Rothstein, J.D.; Borchelt, D.R.; Wong, P.C.; Lin, C.-L.G. Messenger RNA oxidation occurs early in disease pathogenesis and promotes motor neuron degeneration in ALS. PLoS ONE 2008, 3, e2849. [Google Scholar] [CrossRef]
- Becker, L.A.; Huang, B.; Bieri, G.; Ma, R.; Knowles, D.A.; Jafar-Nejad, P.; Messing, J.; Kim, H.J.; Soriano, A.; Auburger, G.; et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 2017, 544, 367–371. [Google Scholar] [CrossRef]
- Elden, A.C.; Kim, H.-J.; Hart, M.P.; Chen-Plotkin, A.S.; Johnson, B.S.; Fang, X.; Armakola, M.; Geser, F.; Greene, R.; Lu, M.M.; et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 2010, 466, 1069–1075. [Google Scholar] [CrossRef]
- Freischmidt, A.; Wieland, T.; Richter, B.; Ruf, W.; Schaeffer, V.; Müller, K.; Marroquin, N.; Nordin, F.; Hübers, A.; Weydt, P.; et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 2015, 18, 631–636. [Google Scholar] [CrossRef] [PubMed]
- Volles, M.J.; Lee, S.J.; Rochet, J.C.; Shtilerman, M.D.; Ding, T.T.; Kessler, J.C.; Lansbury, P.T., Jr. Vesicle permeabilization by protofibrillar alpha-synuclein: Implications for the pathogenesis and treatment of Parkinson’s disease. Biochemistry 2001, 40, 7812–7819. [Google Scholar] [CrossRef] [PubMed]
- Volles, M.J.; Lansbury, P.T., Jr. Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson’s disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 2002, 41, 4595–4602. [Google Scholar] [CrossRef] [PubMed]
- Zakharov, S.D.; Hulleman, J.D.; Dutseva, E.A.; Antonenko, Y.N.; Rochet, J.-C.; Cramer, W.A. Helical alpha-synuclein forms highly conductive ion channels. Biochemistry 2007, 46, 14369–14379. [Google Scholar] [CrossRef] [PubMed]
- Pacheco, C.R.; Morales, C.N.; Ramírez, A.E.; Muñoz, F.J.; Gallegos, S.S.; Caviedes, P.A.; Aguayo, L.G.; Opazo, C.M. Extracellular α-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane. J. Neurochem. 2015, 132, 731–741. [Google Scholar] [CrossRef] [PubMed]
- Scott, D.A.; Tabarean, I.; Tang, Y.; Cartier, A.; Masliah, E.; Roy, S. A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J. Neurosci. 2010, 30, 8083–8095. [Google Scholar] [CrossRef]
- Wersinger, C.; Vernier, P.; Sidhu, A. Trypsin disrupts the trafficking of the human dopamine transporter by alpha-synuclein and its A30P mutant. Biochemistry 2004, 43, 1242–1253. [Google Scholar] [CrossRef]
- Adamczyk, A.; Strosznajder, J.B. Alpha-synuclein potentiates Ca2+ influx through voltage-dependent Ca2+ channels. Neuroreport 2006, 17, 1883–1886. [Google Scholar] [CrossRef]
- Danzer, K.M.; Haasen, D.; Karow, A.R.; Moussaud, S.; Habeck, M.; Giese, A.; Kretzschmar, H.; Hengerer, B.; Kostka, M. Different species of alpha-synuclein oligomers induce calcium influx and seeding. J. Neurosci. 2007, 27, 9220–9232. [Google Scholar] [CrossRef]
- Alim, M.A.; Ma, Q.-L.; Takeda, K.; Aizawa, T.; Matsubara, M.; Nakamura, M.; Asada, A.; Saito, T.; Kaji, H.; Yoshii, M.; et al. Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein. J. Alzheimers. Dis. 2004, 6, 435–442. [Google Scholar] [CrossRef]
- Alim, M.A.; Hossain, M.S.; Arima, K.; Takeda, K.; Izumiyama, Y.; Nakamura, M.; Kaji, H.; Shinoda, T.; Hisanaga, S.; Ueda, K. Tubulin seeds alpha-synuclein fibril formation. J. Biol. Chem. 2002, 277, 2112–2117. [Google Scholar] [CrossRef] [PubMed]
- Lee, H.-J.; Khoshaghideh, F.; Lee, S.; Lee, S.-J. Impairment of microtubule-dependent trafficking by overexpression of alpha-synuclein. Eur. J. Neurosci. 2006, 24, 3153–3162. [Google Scholar] [CrossRef] [PubMed]
- McNaught, K.S.; Jenner, P. Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci. Lett. 2001, 297, 191–194. [Google Scholar] [CrossRef]
- Lindersson, E.; Beedholm, R.; Højrup, P.; Moos, T.; Gai, W.; Hendil, K.B.; Jensen, P.H. Proteasomal inhibition by alpha-synuclein filaments and oligomers. J. Biol. Chem. 2004, 279, 12924–12934. [Google Scholar] [CrossRef]
- Tanaka, Y.; Engelender, S.; Igarashi, S.; Rao, R.K.; Wanner, T.; Tanzi, R.E.; Sawa, A.; Dawson, V.L.; Dawson, T.M.; Ross, C.A. Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum. Mol. Genet. 2001, 10, 919–926. [Google Scholar] [CrossRef]
- Murphy, K.E.; Gysbers, A.M.; Abbott, S.K.; Tayebi, N.; Kim, W.S.; Sidransky, E.; Cooper, A.; Garner, B.; Halliday, G.M. Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson’s disease. Brain 2014, 137, 834–848. [Google Scholar] [CrossRef]
- Papagiannakis, N.; Xilouri, M.; Koros, C.; Stamelou, M.; Antonelou, R.; Maniati, M.; Papadimitriou, D.; Moraitou, M.; Michelakakis, H.; Stefanis, L. Lysosomal alterations in peripheral blood mononuclear cells of Parkinson’s disease patients. Mov. Disord. 2015, 30, 1830–1834. [Google Scholar] [CrossRef]
- Hsu, L.J.; Sagara, Y.; Arroyo, A.; Rockenstein, E.; Sisk, A.; Mallory, M.; Wong, J.; Takenouchi, T.; Hashimoto, M.; Masliah, E. alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am. J. Pathol. 2000, 157, 401–410. [Google Scholar] [CrossRef]
- Devi, L.; Raghavendran, V.; Prabhu, B.M.; Avadhani, N.G.; Anandatheerthavarada, H.K. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J. Biol. Chem. 2008, 283, 9089–9100. [Google Scholar] [CrossRef]
- Colla, E.; Coune, P.; Liu, Y.; Pletnikova, O.; Troncoso, J.C.; Iwatsubo, T.; Schneider, B.L.; Lee, M.K. Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo. J. Neurosci. 2012, 32, 3306–3320. [Google Scholar] [CrossRef]
- Gosavi, N.; Lee, H.-J.; Lee, J.S.; Patel, S.; Lee, S.-J. Golgi fragmentation occurs in the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of fibrillar inclusion. J. Biol. Chem. 2002, 277, 48984–48992. [Google Scholar] [CrossRef] [PubMed]
- Cooper, A.A.; Gitler, A.D.; Cashikar, A.; Haynes, C.M.; Hill, K.J.; Bhullar, B.; Liu, K.; Xu, K.; Strathearn, K.E.; Liu, F.; et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 2006, 313, 324–328. [Google Scholar] [CrossRef] [PubMed]
- Jin, H.; Kanthasamy, A.; Ghosh, A.; Yang, Y.; Anantharam, V.; Kanthasamy, A.G. α-Synuclein negatively regulates protein kinase Cδ expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity. J. Neurosci. 2011, 31, 2035–2051. [Google Scholar] [CrossRef] [PubMed]
- Jin, H.; Kanthasamy, A.; Harischandra, D.S.; Kondru, N.; Ghosh, A.; Panicker, N.; Anantharam, V.; Rana, A.; Kanthasamy, A.G. Histone hyperacetylation up-regulates protein kinase Cδ in dopaminergic neurons to induce cell death: Relevance to epigenetic mechanisms of neurodegeneration in Parkinson disease. J. Biol. Chem. 2014, 289, 34743–34767. [Google Scholar] [CrossRef]
- Kontopoulos, E.; Parvin, J.D.; Feany, M.B. Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum. Mol. Genet. 2006, 15, 3012–3023. [Google Scholar] [CrossRef]
- Xu, X.; Zhuang, C.; Wu, Z.; Qiu, H.; Feng, H.; Wu, J. LincRNA-p21 Inhibits Cell Viability and Promotes Cell Apoptosis in Parkinson’s Disease through Activating α-Synuclein Expression. Biomed. Res. Int. 2018, 2018, 8181374. [Google Scholar] [CrossRef]
- Desplats, P.; Lee, H.-J.; Bae, E.-J.; Patrick, C.; Rockenstein, E.; Crews, L.; Spencer, B.; Masliah, E.; Lee, S.-J. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc. Natl. Acad. Sci. USA 2009, 106, 13010–13015. [Google Scholar] [CrossRef]
- Canale, C.; Seghezza, S.; Vilasi, S.; Carrotta, R.; Bulone, D.; Diaspro, A.; San Biagio, P.L.; Dante, S. Different effects of Alzheimer’s peptide Aβ(1–40) oligomers and fibrils on supported lipid membranes. Biophys. Chem. 2013, 182, 23–29. [Google Scholar] [CrossRef]
- Bode, D.C.; Freeley, M.; Nield, J.; Palma, M.; Viles, J.H. Amyloid-β oligomers have a profound detergent-like effect on lipid membrane bilayers, imaged by atomic force and electron microscopy. J. Biol. Chem. 2019, 294, 7566–7572. [Google Scholar] [CrossRef]
- Hoover, B.R.; Reed, M.N.; Su, J.; Penrod, R.D.; Kotilinek, L.A.; Grant, M.K.; Pitstick, R.; Carlson, G.A.; Lanier, L.M.; Yuan, L.-L.; et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010, 68, 1067–1081. [Google Scholar] [CrossRef]
- Teravskis, P.J.; Oxnard, B.R.; Miller, E.C.; Kemper, L.; Ashe, K.H.; Liao, D. Phosphorylation in two discrete tau domains regulates a stepwise process leading to postsynaptic dysfunction. J. Physiol. 2019. [Google Scholar] [CrossRef] [PubMed]
- Ding, Y.; Zhao, J.; Zhang, X.; Wang, S.; Viola, K.L.; Chow, F.E.; Zhang, Y.; Lippa, C.; Klein, W.L.; Gong, Y. Amyloid Beta Oligomers Target to Extracellular and Intracellular Neuronal Synaptic Proteins in Alzheimer’s Disease. Front. Neurol. 2019, 10, 1140. [Google Scholar] [CrossRef] [PubMed]
- Abd-Elrahman, K.S.; Hamilton, A.; Albaker, A.; Ferguson, S.S.G. mGluR5 Contribution to Neuropathology in Alzheimer Mice Is Disease Stage-Dependent. ACS Pharmacol. Transl. Sci. 2020, 3, 334–344. [Google Scholar] [CrossRef] [PubMed]
- Greotti, E.; Capitanio, P.; Wong, A.; Pozzan, T.; Pizzo, P.; Pendin, D. Familial Alzheimer’s disease-linked presenilin mutants and intracellular Ca handling: A single-organelle, FRET-based analysis. Cell Calcium 2019, 79, 44–56. [Google Scholar] [CrossRef] [PubMed]
- Balducci, C.; Beeg, M.; Stravalaci, M.; Bastone, A.; Sclip, A.; Biasini, E.; Tapella, L.; Colombo, L.; Manzoni, C.; Borsello, T.; et al. Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc. Natl. Acad. Sci. USA 2010, 107, 2295–2300. [Google Scholar] [CrossRef] [PubMed]
- Androuin, A.; Potier, B.; Nägerl, U.V.; Cattaert, D.; Danglot, L.; Thierry, M.; Youssef, I.; Triller, A.; Duyckaerts, C.; El Hachimi, K.H.; et al. Evidence for altered dendritic spine compartmentalization in Alzheimer’s disease and functional effects in a mouse model. Acta Neuropathol. 2018, 135, 839–854. [Google Scholar] [CrossRef] [PubMed]
- Youssef, P.; Chami, B.; Lim, J.; Middleton, T.; Sutherland, G.T.; Witting, P.K. Evidence supporting oxidative stress in a moderately affected area of the brain in Alzheimer’s disease. Sci. Rep. 2018, 8, 11553. [Google Scholar] [CrossRef]
- Majd, S.; Power, J.H.T. Oxidative Stress and Decreased Mitochondrial Superoxide Dismutase 2 and Peroxiredoxins 1 and 4 Based Mechanism of Concurrent Activation of AMPK and mTOR in Alzheimer’s Disease. Curr. Alzheimer Res. 2018, 15, 764–776. [Google Scholar] [CrossRef]
- Wang, J.; Zhao, C.; Zhao, A.; Li, M.; Ren, J.; Qu, X. New insights in amyloid beta interactions with human telomerase. J. Am. Chem. Soc. 2015, 137, 1213–1219. [Google Scholar] [CrossRef]
- Zhang, J.; Kong, Q.; Zhang, Z.; Ge, P.; Ba, D.; He, W. Telomere dysfunction of lymphocytes in patients with Alzheimer disease. Cogn. Behav. Neurol. 2003, 16, 170–176. [Google Scholar] [CrossRef]
- Adav, S.S.; Park, J.E.; Sze, S.K. Quantitative profiling brain proteomes revealed mitochondrial dysfunction in Alzheimer’s disease. Mol. Brain 2019, 12, 8. [Google Scholar] [CrossRef] [PubMed]
- Reddy, P.H.; Yin, X.; Manczak, M.; Kumar, S.; Pradeepkiran, J.A.; Vijayan, M.; Reddy, A.P. Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer’s disease. Hum. Mol. Genet. 2018, 27, 2502–2516. [Google Scholar] [CrossRef] [PubMed]
- Peña-Bautista, C.; López-Cuevas, R.; Cuevas, A.; Baquero, M.; Cháfer-Pericás, C. Lipid peroxidation biomarkers correlation with medial temporal atrophy in early Alzheimer Disease. Neurochem. Int. 2019, 129, 104519. [Google Scholar] [CrossRef] [PubMed]
- Sondag, C.M.; Dhawan, G.; Combs, C.K. Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J. Neuroinflammation 2009, 6, 1. [Google Scholar] [CrossRef] [PubMed]
- Pan, X.-D.; Zhu, Y.-G.; Lin, N.; Zhang, J.; Ye, Q.-Y.; Huang, H.-P.; Chen, X.-C. Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: Implications for Alzheimer’s disease. Mol. Neurodegener. 2011, 6, 45. [Google Scholar] [CrossRef] [PubMed]
- Combs, C.K.; Karlo, J.C.; Kao, S.C.; Landreth, G.E. beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 2001, 21, 1179–1188. [Google Scholar] [CrossRef]
- Finkbeiner, S. Huntington’s Disease. Cold Spring Harb. Perspect. Biol. 2011, 3, a007476. [Google Scholar] [CrossRef]
- Arndt, J.R.; Chaibva, M.; Legleiter, J. The emerging role of the first 17 amino acids of huntingtin in Huntington’s disease. Biomol. Concepts 2015, 6, 33–46. [Google Scholar] [CrossRef]
- Jimenez-Sanchez, M.; Licitra, F.; Underwood, B.R.; Rubinsztein, D.C. Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies. Cold Spring Harb. Perspect. Med. 2017, 7, a024240. [Google Scholar] [CrossRef]
- Kremer, B.; Goldberg, P.; Andrew, S.E.; Theilmann, J.; Telenius, H.; Zeisler, J.; Squitieri, F.; Lin, B.; Bassett, A.; Almqvist, E. A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. N. Engl. J. Med. 1994, 330, 1401–1406. [Google Scholar] [CrossRef]
- Zala, D.; Hinckelmann, M.-V.; Saudou, F. Huntingtin’s function in axonal transport is conserved in Drosophila melanogaster. PLoS ONE 2013, 8, e60162. [Google Scholar] [CrossRef] [PubMed]
- Caviston, J.P.; Ross, J.L.; Antony, S.M.; Tokito, M.; Holzbaur, E.L.F. Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proc. Natl. Acad. Sci. USA 2007, 104, 10045–10050. [Google Scholar] [CrossRef] [PubMed]
- Liot, G.; Zala, D.; Pla, P.; Mottet, G.; Piel, M.; Saudou, F. Mutant Huntingtin alters retrograde transport of TrkB receptors in striatal dendrites. J. Neurosci. 2013, 33, 6298–6309. [Google Scholar] [CrossRef] [PubMed]
- Wong, Y.C.; Holzbaur, E.L.F. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J. Neurosci. 2014, 34, 1293–1305. [Google Scholar] [CrossRef] [PubMed]
- Wu, L.L.-Y.; Fan, Y.; Li, S.; Li, X.-J.; Zhou, X.-F. Huntingtin-associated protein-1 interacts with pro-brain-derived neurotrophic factor and mediates its transport and release. J. Biol. Chem. 2010, 285, 5614–5623. [Google Scholar] [CrossRef] [PubMed]
- Twelvetrees, A.E.; Yuen, E.Y.; Arancibia-Carcamo, I.L.; MacAskill, A.F.; Rostaing, P.; Lumb, M.J.; Humbert, S.; Triller, A.; Saudou, F.; Yan, Z.; et al. Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron 2010, 65, 53–65. [Google Scholar] [CrossRef]
- Elias, S.; Thion, M.S.; Yu, H.; Sousa, C.M.; Lasgi, C.; Morin, X.; Humbert, S. Huntingtin regulates mammary stem cell division and differentiation. Stem Cell Reports 2014, 2, 491–506. [Google Scholar] [CrossRef]
- Reiner, A.; Dragatsis, I.; Zeitlin, S.; Goldowitz, D. Wild-type huntingtin plays a role in brain development and neuronal survival. Mol. Neurobiol. 2003, 28, 259–276. [Google Scholar] [CrossRef]
- Adegbuyiro, A.; Sedighi, F.; Pilkington, A.W., 4th; Groover, S.; Legleiter, J. Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease. Biochemistry 2017, 56, 1199–1217. [Google Scholar]
- Ross, C.A.; Tabrizi, S.J. Huntington’s disease: From molecular pathogenesis to clinical treatment. Lancet Neurol. 2011, 10, 83–98. [Google Scholar] [CrossRef]
- Ambrose, C.M.; Duyao, M.P.; Barnes, G.; Bates, G.P.; Lin, C.S.; Srinidhi, J.; Baxendale, S.; Hummerich, H.; Lehrach, H.; Altherr, M.; et al. Structure and expression of the Huntington’s disease gene: Evidence against simple inactivation due to an expanded CAG repeat. Somat. Cell Mol. Genet. 1994, 20, 27–38. [Google Scholar] [CrossRef] [PubMed]
- Nasir, J.; Floresco, S.B.; O’Kusky, J.R.; Diewert, V.M.; Richman, J.M.; Zeisler, J.; Borowski, A.; Marth, J.D.; Phillips, A.G.; Hayden, M.R. Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 1995, 81, 811–823. [Google Scholar] [CrossRef]
- Zhang, S.; Feany, M.B.; Saraswati, S.; Littleton, J.T.; Perrimon, N. Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington’s disease model. Dis. Model. Mech. 2009, 2, 247–266. [Google Scholar] [CrossRef] [PubMed]
- Zeitler, B.; Froelich, S.; Marlen, K.; Shivak, D.A.; Yu, Q.; Li, D.; Pearl, J.R.; Miller, J.C.; Zhang, L.; Paschon, D.E.; et al. Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nat. Med. 2019, 25, 1131–1142. [Google Scholar] [CrossRef] [PubMed]
- Tabrizi, S.J.; Leavitt, B.R.; Landwehrmeyer, G.B.; Wild, E.J.; Saft, C.; Barker, R.A.; Blair, N.F.; Craufurd, D.; Priller, J.; Rickards, H.; et al. Targeting Huntingtin Expression in Patients with Huntington’s Disease. N. Engl. J. Med. 2019, 380, 2307–2316. [Google Scholar] [CrossRef]
- Kiernan, M.C.; Vucic, S.; Cheah, B.C.; Turner, M.R.; Eisen, A.; Hardiman, O.; Burrell, J.R.; Zoing, M.C. Amyotrophic lateral sclerosis. Lancet 2011, 377, 942–955. [Google Scholar] [CrossRef]
- Prasad, A.; Bharathi, V.; Sivalingam, V.; Girdhar, A.; Patel, B.K. Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis. Front. Mol. Neurosci. 2019, 12, 25. [Google Scholar] [CrossRef]
- Geuens, T.; Bouhy, D.; Timmerman, V. The hnRNP family: Insights into their role in health and disease. Hum. Genet. 2016, 135, 851–867. [Google Scholar] [CrossRef]
- Afroz, T.; Hock, E.-M.; Ernst, P.; Foglieni, C.; Jambeau, M.; Gilhespy, L.A.B.; Laferriere, F.; Maniecka, Z.; Plückthun, A.; Mittl, P.; et al. Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation. Nat. Commun. 2017, 8, 45. [Google Scholar] [CrossRef]
- Afroz, T.; Pérez-Berlanga, M.; Polymenidou, M. Structural Transition, Function and Dysfunction of TDP-43 in Neurodegenerative Diseases. Chimia 2019, 73, 380–390. [Google Scholar] [CrossRef]
- Baskaran, P.; Shaw, C.; Guthrie, S. TDP-43 causes neurotoxicity and cytoskeletal dysfunction in primary cortical neurons. PLoS ONE 2018, 13, e0196528. [Google Scholar] [CrossRef] [PubMed]
- Hergesheimer, R.C.; Chami, A.A.; De Assis, D.R.; Vourc’h, P.; Andres, C.R.; Corcia, P.; Lanznaster, D.; Blasco, H. The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: A resolution in sight? Brain 2019, 142, 1176–1194. [Google Scholar] [CrossRef] [PubMed]
- Sun, Y.; Chakrabartty, A. Phase to Phase with TDP-43. Biochemistry 2017, 56, 809–823. [Google Scholar] [PubMed]
- Ishigaki, S.; Sobue, G. Importance of Functional Loss of FUS in FTLD/ALS. Front. Mol. Biosci. 2018, 5, 44. [Google Scholar] [CrossRef] [PubMed]
- Lindström, M.; Liu, B. Yeast as a Model to Unravel Mechanisms Behind FUS Toxicity in Amyotrophic Lateral Sclerosis. Front. Mol. Neurosci. 2018, 11, 218. [Google Scholar] [CrossRef]
- Kaur, S.J.; McKeown, S.R.; Rashid, S. Mutant SOD1 mediated pathogenesis of Amyotrophic Lateral Sclerosis. Gene 2016, 577, 109–118. [Google Scholar] [CrossRef] [PubMed]
- Zarei, S.; Carr, K.; Reiley, L.; Diaz, K.; Guerra, O.; Altamirano, P.F.; Pagani, W.; Lodin, D.; Orozco, G.; Chinea, A. A comprehensive review of amyotrophic lateral sclerosis. Surg. Neurol. Int. 2015, 6, 171. [Google Scholar] [CrossRef]
- Silverman, J.M.; Fernando, S.M.; Grad, L.I.; Hill, A.F.; Turner, B.J.; Yerbury, J.J.; Cashman, N.R. Disease Mechanisms in ALS: Misfolded SOD1 Transferred Through Exosome-Dependent and Exosome-Independent Pathways. Cell. Mol. Neurobiol. 2016, 36, 377–381. [Google Scholar] [CrossRef]
- Oakes, J.A.; Davies, M.C.; Collins, M.O. TBK1: A new player in ALS linking autophagy and neuroinflammation. Mol. Brain 2017, 10, 5. [Google Scholar] [CrossRef]
- Prasad, A.; Raju, G.; Sivalingam, V.; Girdhar, A.; Verma, M.; Vats, A.; Taneja, V.; Prabusankar, G.; Patel, B.K. An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models. Sci. Rep. 2016, 6, 39490. [Google Scholar] [CrossRef]
- Cassel, J.A.; McDonnell, M.E.; Velvadapu, V.; Andrianov, V.; Reitz, A.B. Characterization of a series of 4-aminoquinolines that stimulate caspase-7 mediated cleavage of TDP-43 and inhibit its function. Biochimie 2012, 94, 1974–1981. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Jackrel, M.E.; DeSantis, M.E.; Martinez, B.A.; Castellano, L.M.; Stewart, R.M.; Caldwell, K.A.; Caldwell, G.A.; Shorter, J. Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell 2014, 156, 170–182. [Google Scholar] [CrossRef] [PubMed]
- Yoshizawa, T.; Ali, R.; Jiou, J.; Fung, H.Y.J.; Burke, K.A.; Kim, S.J.; Lin, Y.; Peeples, W.B.; Saltzberg, D.; Soniat, M.; et al. Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites. Cell 2018, 173, 693–705.e22. [Google Scholar] [CrossRef] [PubMed]
- Weiss, M.D.; Macklin, E.A.; Simmons, Z.; Knox, A.S.; Greenblatt, D.J.; Atassi, N.; Graves, M.; Parziale, N.; Salameh, J.S.; Quinn, C.; et al. A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression. Neurology 2016, 86, 1474–1481. [Google Scholar] [CrossRef] [PubMed]
- Takei, K.; Watanabe, K.; Yuki, S.; Akimoto, M.; Sakata, T.; Palumbo, J. Edaravone and its clinical development for amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal. Degener. 2017, 18, 5–10. [Google Scholar] [CrossRef] [PubMed]
- Mandrioli, J.; D’Amico, R.; Zucchi, E.; Gessani, A.; Fini, N.; Fasano, A.; Caponnetto, C.; Chiò, A.; Dalla Bella, E.; Lunetta, C.; et al. Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial). Medicine 2018, 97, e11119. [Google Scholar] [CrossRef]
- Takahashi, S.; Morimoto, S.; Okano, H. Ropinirole Hydrochloride, a Candidate Drug for ALS Treatment. Brain Nerve 2019, 71, 943–952. [Google Scholar]
- Chen, P.-C.; Hsieh, Y.-C.; Huang, C.-C.; Hu, C.-J. Tamoxifen for amyotrophic lateral sclerosis: A randomized double-blind clinical trial. Medicine 2020, 99, e20423. [Google Scholar] [CrossRef]
- Benatar, M.; Wuu, J.; Andersen, P.M.; Atassi, N.; David, W.; Cudkowicz, M.; Schoenfeld, D. Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive ALS. Neurology 2018, 90, e565–e574. [Google Scholar] [CrossRef]
- Polymeropoulos, M.H.; Lavedan, C.; Leroy, E.; Ide, S.E.; Dehejia, A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R.; et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997, 276, 2045–2047. [Google Scholar] [CrossRef]
- Spillantini, M.G.; Crowther, R.A.; Jakes, R.; Hasegawa, M.; Goedert, M. Alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc. Natl. Acad. Sci. USA 1998, 95, 6469–6473. [Google Scholar] [CrossRef] [PubMed]
- Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.; Trojanowski, J.Q.; Jakes, R.; Goedert, M. Alpha-synuclein in Lewy bodies. Nature 1997, 388, 839–840. [Google Scholar] [CrossRef] [PubMed]
- Klingelhoefer, L.; Reichmann, H. Parkinson’s disease as a multisystem disorder. J. Neural. Transm. 2017, 124, 709–713. [Google Scholar] [CrossRef] [PubMed]
- Angot, E.; Brundin, P. Dissecting the potential molecular mechanisms underlying alpha-synuclein cell-to-cell transfer in Parkinson’s disease. Parkinsonism Relat. Disord. 2009, 15, S143–S147. [Google Scholar] [CrossRef]
- Burré, J.; Sharma, M.; Tsetsenis, T.; Buchman, V.; Etherton, M.R.; Südhof, T.C. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 2010, 329, 1663–1667. [Google Scholar] [CrossRef]
- Surguchov, A. Molecular and cellular biology of synucleins. Int. Rev. Cell Mol. Biol. 2008, 270, 225–317. [Google Scholar]
- Cheng, F.; Vivacqua, G.; Yu, S. The role of α-synuclein in neurotransmission and synaptic plasticity. J. Chem. Neuroanat. 2011, 42, 242–248. [Google Scholar] [CrossRef]
- Benskey, M.J.; Perez, R.G.; Manfredsson, F.P. The contribution of alpha synuclein to neuronal survival and function—Implications for Parkinson’s disease. J. Neurochem. 2016, 137, 331–359. [Google Scholar] [CrossRef]
- Uéda, K.; Fukushima, H.; Masliah, E.; Xia, Y.; Iwai, A.; Yoshimoto, M.; Otero, D.A.; Kondo, J.; Ihara, Y.; Saitoh, T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 1993, 90, 11282–11286. [Google Scholar] [CrossRef]
- Park, S.M.; Jung, H.Y.; Chung, K.C.; Rhim, H.; Park, J.H.; Kim, J. Stress-induced aggregation profiles of GST-alpha-synuclein fusion proteins: Role of the C-terminal acidic tail of alpha-synuclein in protein thermosolubility and stability. Biochemistry 2002, 41, 4137–4146. [Google Scholar] [CrossRef]
- Park, S.M.; Ahn, K.J.; Jung, H.Y.; Park, J.H.; Kim, J. Effects of novel peptides derived from the acidic tail of synuclein (ATS) on the aggregation and stability of fusion proteins. Protein Eng. Des. Sel. 2004, 17, 251–260. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Bartels, T.; Choi, J.G.; Selkoe, D.J. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 2011, 477, 107–110. [Google Scholar] [CrossRef] [PubMed]
- Binolfi, A.; Theillet, F.-X.; Selenko, P. Bacterial in-cell NMR of human α-synuclein: A disordered monomer by nature? Biochem. Soc. Trans. 2012, 40, 950–954. [Google Scholar] [CrossRef] [PubMed]
- Fauvet, B.; Mbefo, M.K.; Fares, M.-B.; Desobry, C.; Michael, S.; Ardah, M.T.; Tsika, E.; Coune, P.; Prudent, M.; Lion, N.; et al. α-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J. Biol. Chem. 2012, 287, 15345–15364. [Google Scholar] [CrossRef] [PubMed]
- Wood, S.J.; Wypych, J.; Steavenson, S.; Louis, J.C.; Citron, M.; Biere, A.L. Alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson’s disease. J. Biol. Chem. 1999, 274, 19509–19512. [Google Scholar] [CrossRef]
- Lee, C.-C.; Nayak, A.; Sethuraman, A.; Belfort, G.; McRae, G.J. A three-stage kinetic model of amyloid fibrillation. Biophys. J. 2007, 92, 3448–3458. [Google Scholar] [CrossRef]
- Eisele, Y.S.; Monteiro, C.; Fearns, C.; Encalada, S.E.; Wiseman, R.L.; Powers, E.T.; Kelly, J.W. Targeting protein aggregation for the treatment of degenerative diseases. Nat. Rev. Drug Discov. 2015, 14, 759–780. [Google Scholar] [CrossRef]
- Narhi, L.; Wood, S.J.; Steavenson, S.; Jiang, Y.; Wu, G.M.; Anafi, D.; Kaufman, S.A.; Martin, F.; Sitney, K.; Denis, P.; et al. Both familial Parkinson’s disease mutations accelerate alpha-synuclein aggregation. J. Biol. Chem. 1999, 274, 9843–9846. [Google Scholar] [CrossRef]
- Conway, K.A.; Lee, S.J.; Rochet, J.C.; Ding, T.T.; Williamson, R.E.; Lansbury, P.T., Jr. Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: Implications for pathogenesis and therapy. Proc. Natl. Acad. Sci. USA 2000, 97, 571–576. [Google Scholar] [CrossRef]
- Breydo, L.; Wu, J.W.; Uversky, V.N. A-synuclein misfolding and Parkinson’s disease. Biochim. Biophys. Acta 2012, 1822, 261–285. [Google Scholar] [CrossRef]
- Goers, J.; Manning-Bog, A.B.; McCormack, A.L.; Millett, I.S.; Doniach, S.; Di Monte, D.A.; Uversky, V.N.; Fink, A.L. Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry 2003, 42, 8465–8471. [Google Scholar] [CrossRef] [PubMed]
- Van Rooijen, B.D.; Claessens, M.M.A.E.; Subramaniam, V. Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism. PLoS ONE 2010, 5, e14292. [Google Scholar] [CrossRef] [PubMed]
- Tosatto, L.; Andrighetti, A.O.; Plotegher, N.; Antonini, V.; Tessari, I.; Ricci, L.; Bubacco, L.; Dalla Serra, M. Alpha-synuclein pore forming activity upon membrane association. Biochim. Biophys. Acta 2012, 1818, 2876–2883. [Google Scholar] [CrossRef] [PubMed]
- Tsigelny, I.F.; Sharikov, Y.; Wrasidlo, W.; Gonzalez, T.; Desplats, P.A.; Crews, L.; Spencer, B.; Masliah, E. Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation. FEBS J. 2012, 279, 1000–1013. [Google Scholar] [CrossRef]
- Lashuel, H.A.; Overk, C.R.; Oueslati, A.; Masliah, E. The many faces of α-synuclein: From structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 2013, 14, 38–48. [Google Scholar] [CrossRef]
- Gan-Or, Z.; Dion, P.A.; Rouleau, G.A. Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 2015, 11, 1443–1457. [Google Scholar] [CrossRef]
- Chu, Y.; Dodiya, H.; Aebischer, P.; Olanow, C.W.; Kordower, J.H. Alterations in lysosomal and proteasomal markers in Parkinson’s disease: Relationship to alpha-synuclein inclusions. Neurobiol. Dis. 2009, 35, 385–398. [Google Scholar] [CrossRef]
- Liu, G.; Zhang, C.; Yin, J.; Li, X.; Cheng, F.; Li, Y.; Yang, H.; Uéda, K.; Chan, P.; Yu, S. α-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity. Neurosci. Lett. 2009, 454, 187–192. [Google Scholar] [CrossRef]
- Mullin, S.; Smith, L.; Lee, K.; D’Souza, G.; Woodgate, P.; Elflein, J.; Hällqvist, J.; Toffoli, M.; Streeter, A.; Hosking, J.; et al. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. 2020, 77, 427–434. [Google Scholar] [CrossRef]
- McFarthing, K.; Simuni, T. Clinical Trial Highlights: Targetting α-Synuclein. J. Parkinsons. Dis. 2019, 9, 5–16. [Google Scholar] [CrossRef]
- Schenk, D.B.; Koller, M.; Ness, D.K.; Griffith, S.G.; Grundman, M.; Zago, W.; Soto, J.; Atiee, G.; Ostrowitzki, S.; Kinney, G.G. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov. Disord. 2017, 32, 211–218. [Google Scholar] [CrossRef] [PubMed]
- Jankovic, J.; Goodman, I.; Safirstein, B.; Marmon, T.K.; Schenk, D.B.; Koller, M.; Zago, W.; Ness, D.K.; Griffith, S.G.; Grundman, M.; et al. Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol. 2018, 75, 1206–1214. [Google Scholar] [CrossRef] [PubMed]
- Brys, M.; Fanning, L.; Hung, S.; Ellenbogen, A.; Penner, N.; Yang, M.; Welch, M.; Koenig, E.; David, E.; Fox, T.; et al. Randomized phase I clinical trial of anti-α-synuclein antibody BIIB054. Mov. Disord. 2019, 34, 1154–1163. [Google Scholar] [CrossRef] [PubMed]
- Crous-Bou, M.; Minguillón, C.; Gramunt, N.; Molinuevo, J.L. Alzheimer’s disease prevention: From risk factors to early intervention. Alzheimers. Res. Ther. 2017, 9, 71. [Google Scholar] [CrossRef] [PubMed]
- 2020 Alzheimer’s disease facts and figures. Alzheimers. Dement. 2020. [CrossRef]
- Di Resta, C.; Ferrari, M. New molecular approaches to Alzheimer’s disease. Clin. Biochem. 2019, 72, 81–86. [Google Scholar] [CrossRef]
- Long, J.M.; Holtzman, D.M. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell 2019, 179, 312–339. [Google Scholar] [CrossRef]
- Hampel, H.; Vassar, R.; De Strooper, B.; Hardy, J.; Willem, M.; Singh, N.; Zhou, J.; Yan, R.; Vanmechelen, E.; De Vos, A.; et al. The β-Secretase BACE1 in Alzheimer’s Disease. Biol. Psychiatry 2020. [Google Scholar] [CrossRef]
- Colvin, M.T.; Silvers, R.; Ni, Q.Z.; Can, T.V.; Sergeyev, I.; Rosay, M.; Donovan, K.J.; Michael, B.; Wall, J.; Linse, S.; et al. Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils. J. Am. Chem. Soc. 2016, 138, 9663–9674. [Google Scholar] [CrossRef]
- Riek, R.; Eisenberg, D.S. The activities of amyloids from a structural perspective. Nature 2016, 539, 227–235. [Google Scholar] [CrossRef]
- Yamamoto, N.; Tsuhara, S.; Tamura, A.; Chatani, E. A specific form of prefibrillar aggregates that functions as a precursor of amyloid nucleation. Sci. Rep. 2018, 8, 62. [Google Scholar] [CrossRef] [PubMed]
- Morris, C.; Cupples, S.; Kent, T.W.; Elbassal, E.A.; Wojcikiewicz, E.P.; Yi, P.; Du, D. N-Terminal Charged Residues of Amyloid-β Peptide Modulate Amyloidogenesis and Interaction with Lipid Membrane. Chemistry 2018, 24, 9494–9498. [Google Scholar] [CrossRef] [PubMed]
- Sciacca, M.F.M.; Kotler, S.A.; Brender, J.R.; Chen, J.; Lee, D.-K.; Ramamoorthy, A. Two-step mechanism of membrane disruption by Aβ through membrane fragmentation and pore formation. Biophys. J. 2012, 103, 702–710. [Google Scholar] [CrossRef] [PubMed]
- Groemer, T.W.; Thiel, C.S.; Holt, M.; Riedel, D.; Hua, Y.; Hüve, J.; Wilhelm, B.G.; Klingauf, J. Amyloid precursor protein is trafficked and secreted via synaptic vesicles. PLoS ONE 2011, 6, e18754. [Google Scholar] [CrossRef] [PubMed]
- Jiang, S.; Li, Y.; Zhang, X.; Bu, G.; Xu, H.; Zhang, Y.-W. Trafficking regulation of proteins in Alzheimer’s disease. Mol. Neurodegener. 2014, 9, 6. [Google Scholar] [CrossRef]
- Müller, U.C.; Deller, T.; Korte, M. Not just amyloid: Physiological functions of the amyloid precursor protein family. Nat. Rev. Neurosci. 2017, 18, 281–298. [Google Scholar] [CrossRef]
- Deyts, C.; Thinakaran, G.; Parent, A.T. APP Receptor? To Be or Not To Be. Trends Pharmacol. Sci. 2016, 37, 390–411. [Google Scholar] [CrossRef]
- Morrissey, J.A.; Mockett, B.G.; Singh, A.; Kweon, D.; Ohline, S.M.; Tate, W.P.; Hughes, S.M.; Abraham, W.C. A C-terminal peptide from secreted amyloid precursor protein-α enhances long-term potentiation in rats and a transgenic mouse model of Alzheimer’s disease. Neuropharmacology 2019, 157, 107670. [Google Scholar] [CrossRef]
- Rice, H.C.; De Malmazet, D.; Schreurs, A.; Frere, S.; Van Molle, I.; Volkov, A.N.; Creemers, E.; Vertkin, I.; Nys, J.; Ranaivoson, F.M.; et al. Secreted amyloid-β precursor protein functions as a GABAR1a ligand to modulate synaptic transmission. Science 2019, 363, eaao4827. [Google Scholar] [CrossRef]
- Gulisano, W.; Melone, M.; Li Puma, D.D.; Tropea, M.R.; Palmeri, A.; Arancio, O.; Grassi, C.; Conti, F.; Puzzo, D. The effect of amyloid-β peptide on synaptic plasticity and memory is influenced by different isoforms, concentrations, and aggregation status. Neurobiol. Aging 2018, 71, 51–60. [Google Scholar] [CrossRef]
- Gulisano, W.; Melone, M.; Ripoli, C.; Tropea, M.R.; Li Puma, D.D.; Giunta, S.; Cocco, S.; Marcotulli, D.; Origlia, N.; Palmeri, A.; et al. Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory. J. Neurosci. 2019, 39, 5986–6000. [Google Scholar] [CrossRef] [PubMed]
- Novo, M.; Freire, S.; Al-Soufi, W. Critical aggregation concentration for the formation of early Amyloid-β (1–42) oligomers. Sci. Rep. 2018, 8, 1783. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.-Q.; Mobley, W.C. Alzheimer Disease Pathogenesis: Insights From Molecular and Cellular Biology Studies of Oligomeric Aβ and Tau Species. Front. Neurosci. 2019, 13, 659. [Google Scholar] [CrossRef] [PubMed]
- Sakono, M.; Zako, T. Amyloid oligomers: Formation and toxicity of Abeta oligomers. FEBS J. 2010, 277, 1348–1358. [Google Scholar] [CrossRef] [PubMed]
- Boland, B.; Yu, W.H.; Corti, O.; Mollereau, B.; Henriques, A.; Bezard, E.; Pastores, G.M.; Rubinsztein, D.C.; Nixon, R.A.; Duchen, M.R.; et al. Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nat. Rev. Drug Discov. 2018, 17, 660–688. [Google Scholar] [CrossRef]
- Nixon, R.A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: Inseparable partners in a multifactorial disease. FASEB J. 2017, 31, 2729–2743. [Google Scholar] [CrossRef]
- Chakravorty, A.; Jetto, C.T.; Manjithaya, R. Dysfunctional Mitochondria and Mitophagy as Drivers of Alzheimer’s Disease Pathogenesis. Front. Aging Neurosci. 2019, 11, 311. [Google Scholar] [CrossRef]
- Mroczko, B.; Groblewska, M.; Litman-Zawadzka, A. The Role of Protein Misfolding and Tau Oligomers (TauOs) in Alzheimer’s Disease (AD). Int. J. Mol. Sci. 2019, 20, 4661. [Google Scholar] [CrossRef]
- Goedert, M.; Spillantini, M.G.; Jakes, R.; Rutherford, D.; Crowther, R.A. Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 1989, 3, 519–526. [Google Scholar] [CrossRef]
- Dixit, R.; Ross, J.L.; Goldman, Y.E.; Holzbaur, E.L.F. Differential regulation of dynein and kinesin motor proteins by tau. Science 2008, 319, 1086–1089. [Google Scholar] [CrossRef]
- Dubey, M.; Chaudhury, P.; Kabiru, H.; Shea, T.B. Tau inhibits anterograde axonal transport and perturbs stability in growing axonal neurites in part by displacing kinesin cargo: Neurofilaments attenuate tau-mediated neurite instability. Cell Motil. Cytoskeleton 2008, 65, 89–99. [Google Scholar] [CrossRef] [PubMed]
- Ittner, A.; Ittner, L.M. Dendritic Tau in Alzheimer’s Disease. Neuron 2018, 99, 13–27. [Google Scholar] [CrossRef] [PubMed]
- Violet, M.; Delattre, L.; Tardivel, M.; Sultan, A.; Chauderlier, A.; Caillierez, R.; Talahari, S.; Nesslany, F.; Lefebvre, B.; Bonnefoy, E.; et al. A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front. Cell. Neurosci. 2014, 8, 84. [Google Scholar] [CrossRef] [PubMed]
- Marciniak, E.; Leboucher, A.; Caron, E.; Ahmed, T.; Tailleux, A.; Dumont, J.; Issad, T.; Gerhardt, E.; Pagesy, P.; Vileno, M.; et al. Tau deletion promotes brain insulin resistance. J. Exp. Med. 2017, 214, 2257–2269. [Google Scholar] [CrossRef] [PubMed]
- Alonso, A.; Zaidi, T.; Novak, M.; Grundke-Iqbal, I.; Iqbal, K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc. Natl. Acad. Sci. USA 2001, 98, 6923–6928. [Google Scholar] [CrossRef]
- Tai, H.-C.; Wang, B.Y.; Serrano-Pozo, A.; Frosch, M.P.; Spires-Jones, T.L.; Hyman, B.T. Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer’s disease. Acta Neuropathol. Commun. 2014, 2, 146. [Google Scholar] [CrossRef] [PubMed]
- Sevigny, J.; Chiao, P.; Bussière, T.; Weinreb, P.H.; Williams, L.; Maier, M.; Dunstan, R.; Salloway, S.; Chen, T.; Ling, Y.; et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016, 537, 50–56. [Google Scholar] [CrossRef]
- Klein, G.; Delmar, P.; Voyle, N.; Rehal, S.; Hofmann, C.; Abi-Saab, D.; Andjelkovic, M.; Ristic, S.; Wang, G.; Bateman, R.; et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: A PET substudy interim analysis. Alzheimers. Res. Ther. 2019, 11, 101. [Google Scholar] [CrossRef]
- Zhao, X.; Rebeck, G.W.; Hoe, H.-S.; Andrews, P.M. Tarenflurbil protection from cytotoxicity is associated with an upregulation of neurotrophins. J. Alzheimers. Dis. 2008, 15, 397–407. [Google Scholar] [CrossRef]
- Green, R.C.; Schneider, L.S.; Amato, D.A.; Beelen, A.P.; Wilcock, G.; Swabb, E.A.; Zavitz, K.H.; Tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial. JAMA 2009, 302, 2557–2564. [Google Scholar] [CrossRef]
- Van Bulck, M.; Sierra-Magro, A.; Alarcon-Gil, J.; Perez-Castillo, A.; Morales-Garcia, J.A. Novel Approaches for the Treatment of Alzheimer’s and Parkinson’s Disease. Int. J. Mol. Sci. 2019, 20, E719. [Google Scholar] [CrossRef] [PubMed]
Neurodegenerative Disease | Protein Aggregates | IDR Protein Structure | Species Location | Toxicity | References |
---|---|---|---|---|---|
Huntington’s disease | Huntingtin | PolyQ | Intracellular (cytosolic and nuclear) | Plasma-membrane integrity disruption Transcriptional dysregulation Reduced levels of neurotrophic factors as BDNF Impairment of protein degradation systems Mitochondrial dysfunction Reactive gliosis Neuroinflammation Cell death | [4] [5] [6] [7,8] [9,10] [11] [12] [13] |
Amyotrophic Lateral Sclerosis | TPD-43 | C-Terminal Domain | Cytoplasmic aggregate | Affected mRNA splicing and RNA metabolism proteins Global protein synthesis inhibition Mitochondrial impairment Defective autophagy lysosomal pathway Endocytosis impairment Dysregulated metal ions (as zinc and manganese) Alteration in chromatin dynamics | [14,15] [16] [17,18] [19,20,21] [22,23] [24,25] [26] |
FUS | N-Terminal domain | Affected mRNA metabolism and DNA reparation Defects in Protein Quality Control (PQC) system | [27] [28] | ||
SOD-1 | 22–30,55–95 region 121–143 region | Excitotoxity linked to glutamate transporter EAAT2 Excessive calcium influx Mitochondrial dysfunction Compromised axonal transport ROS cytotoxicity RNA species damaged | [29,30] [29,30] [31,32,33] [34,35,36] [37] [38] | ||
Ataxin-2 | PolyQ tract | Stress response dysfunction Affected RNA metabolism | [39] [40] | ||
TBK-1 | TBK-1 | Autophagy dysfunction | [41] | ||
Parkinson’s disease | α-Synuclein | C-terminal domain | Intracellular LBs formation, extracellular and membrane | Plasma-membrane integrity disruption Synapse alteration Perturbation in calcium homeostasis Cytoskeleton dynamics altered Protein degradation system dysfunction Lysosomal impact Mitochondrial dysfunction and ROS induction Endoplasmic reticulum stress Golgi transmission affected Modified histone acetylation procedures Apoptosis | [42,43,44,45] [46,47] [48,49] [50,51,52] [53,54,55] [55,56,57] [58,59] [59,60] [61,62] [63,64,65] [66,67] |
Alzheimer’s disease | Amyloid-β | Amyloid-β | Extracellular plaques | Plasma-membrane alteration Perturbed synaptic function and structure Glial cells perturbation via mGluR5 receptor Altered calcium homeostasis LTP inhibition in the CA1 region of the hippocampus Oxidative stress disfunction | [68,69] [70,71,72] [73] [74] [75,76] [77,78] |
Tau | N-terminal domain | Intracellular neurofibrillary tangles | Telomerase dysfunction Mitochondrial damage and ROS Lipid peroxidation Activated microglia leading to neuronal phagocytosis Apoptosis | [79,80] [81,82] [83] [84,85] [86] |
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Ruz, C.; Alcantud, J.L.; Vives Montero, F.; Duran, R.; Bandres-Ciga, S. Proteotoxicity and Neurodegenerative Diseases. Int. J. Mol. Sci. 2020, 21, 5646. https://doi.org/10.3390/ijms21165646
Ruz C, Alcantud JL, Vives Montero F, Duran R, Bandres-Ciga S. Proteotoxicity and Neurodegenerative Diseases. International Journal of Molecular Sciences. 2020; 21(16):5646. https://doi.org/10.3390/ijms21165646
Chicago/Turabian StyleRuz, Clara, Jose Luis Alcantud, Francisco Vives Montero, Raquel Duran, and Sara Bandres-Ciga. 2020. "Proteotoxicity and Neurodegenerative Diseases" International Journal of Molecular Sciences 21, no. 16: 5646. https://doi.org/10.3390/ijms21165646
APA StyleRuz, C., Alcantud, J. L., Vives Montero, F., Duran, R., & Bandres-Ciga, S. (2020). Proteotoxicity and Neurodegenerative Diseases. International Journal of Molecular Sciences, 21(16), 5646. https://doi.org/10.3390/ijms21165646