Protein Misfolding and Aggregation: The Relatedness between Parkinson’s Disease and Hepatic Endoplasmic Reticulum Storage Disorders
Abstract
:1. Introduction
2. Alpha-Synuclein
2.1. Alpha-Synuclein Aggregation Induces Parkinson’s Disease
2.2. Alpha-Synuclein Aggregation in the Cell
2.3. Physiological Response to α-Syn Aggregation: Autophagy and Proteosomes
3. Alpha-1-Antitrypsin
3.1. Alpha-1-Antitrypsin Aggregation Induces Serpinopathies
3.2. Z-AAT Aggregation in the Cell
3.3. Physiological Response to Z-AAT Aggregation: Autophagy and Proteosomes
4. Fibrinogen
4.1. Fibrinogen Aggregation Induces Coagulopathies
4.2. FG Aggregation in the Cell
4.3. Physiological Response to FG Aggregation: Autophagy and Proteosomes
5. Endoplasmic Reticulum Stress and Unfolded Protein Response
5.1. The ER and the ER Stress
5.2. The Unfolded Protein Response
5.3. ER Stress and UPR in PD
5.4. ER Stress and UPR in AATD
5.5. ER Stress and UPR in HHHS
6. Hallmark Findings Comparison
7. Clinical Perspectives
7.1. Proteolytic Pathways Induction as Potential Treatment for α-Syn Aggregation in PD
Parkinson’s Disease | ||||
---|---|---|---|---|
Target | Strategy | Results * | Conclusions | Ref. |
ER stress | Transgenic mice over-expressing WT or mutant (A53T and A30P) α-syn treated with Salubrinal | ↓ α-syn oligomer ↓ ER stress | α -syn oligomers cause neurodegeneration by chronic ER stress response in vivo | [171] |
ER stress | Mithramycin (MTM) administration in organotypic hippocampal slice cultures | ↓ ER stress-induced neurotoxicity ↓ Cell death by CHOP inhibition | MTM is a protective agent against ER stress neuronal death in vitro | [214] |
ER stress | Tangeretin administration in mice injected with tunicamycin | ↑ Expression of GRP78 in SNpc ↓ Cell death induced by MPTP | Tangeretin regulates ER stress-related to PD | [223] |
ER stress and UPR | Genetic deletion of ATF6α in transgenic mice treated with MPTP | ↓ TH levels and ↓ Number of dopaminergic neurons in SNpc | ATF6α exerts neuroprotection of dopaminergic neurons from MPTP toxicity in vivo | [218] |
ER stress and UPR | Mouse model with deletion of ATF6α gene and injection of MPTP and probenecid (MPTP/P) | ↓ GRP78 ↑ Neuronal degeneration ↑ Ubiquitin accumulation ↓ Astroglial activation ↓ BDNF ↓ Anti-oxidative genes ↓ CHOP | UPR is activated in a model of chronic MPTP/P injection causing neurodegeneration | [219] |
ER stress and UPR | Administration of tangeretin into mice with deletion of ATF6α and MPTP/P | ↑ UPR-target genes ↑ Dopaminergic neuronal survival ↑ Astrocyte survival | UPR contributes to the survival of dopaminergic neurons in SNpc | [219] |
ER stress and UPR | Overexpression of chaperones GRP78/BiP in α-syn rat model of PD | ↓ α-syn neurotoxicity ↓ Apoptosis in TH neurons of SNpc ↑ Levels of striatal dopamine release | The GRP78/BiP plays a neuroprotective role in α-syn neurodegeneration | [220] |
Macroautophagy | Overexpression of α-syn in cell cultures (SKNSH, HeLa and HEK293 lines) | ↑ p62 and ↓ LC3-II ↓ RAB1 homeostasis ↓ Omegasome formation Mislocalization of ATG-9 | Rab1a, α-syn, and ATG-9 regulate the formation of Omegasome | [60] |
Autophagy–lysosome system | Overexpression of α-syn by lentivirus transduction and co-expression of Beclin-1 in a neuronal cell line | ↓ Accumulation of α-syn ↓ Neuritic alterations ↑ Effects of Beclin-1 by Rapamycin ↑ Lysosomal activation ↓ Synaptic and dendritic pathology ↓ Alterations in autophagy pathway | Beclin-1 decreases neuronal pathology of α-syn by inducing autophagy in vitro | [174] |
Macroautophagy | Induction of macroautophagy by administration of trehalose in A53T α-syn transgenic rats | ↓ α-syn accumulation and aggregation in SNpc ↓ α-syn deficits in motor asymmetry ↑ Survival of dopaminergic neurons ↑ Dopamine turnover | Induction of macroutophagy prevents/ reverse α-syn aggregation in models of PD | [230] |
CMA | Overexpression of LAMP2A in SH-SY5Y cells, rat cortical neurons in vitro, and SNpc neurons in vivo | ↓ α-syn neurotoxicity ↑ Survival of SNpc dopaminergic neurons ↑ Functionality of dopaminergic striatal terminals | Induction of CMA provide a novel therapeutic strategy for treatment of PD | [232] |
Autophagy–lysosome system | Overexpressing of GCase in A53T α-syn transgenic mice | ↓ Soluble α-syn levels | GCase represents a potential therapeutic strategy for PD | [233] |
7.2. Proteolytic Pathways Induction as Potential Treatment for AAT Aggregation in AATD
α-1-Antitrypsin Deficiency | ||||
---|---|---|---|---|
Target | Strategy | Results * | Conclusions | Ref. |
Block polymerization of Z-AAT | Administration of 6-Mer reactive loop peptide (FLEAIG) | ↓ Polymerization of Z- AAT | Small molecule inhibitors can be used to treat Z-AAT deficiency. | [245] |
ER stress and UPR | Administration of modulators of UPR: Sarcosine, Betaine, Hydroxyectoine and Ectoine in ER-stress induced by Tunicamycin | ↑ Restoration of homeostasis ↓ Levels of GRP78 and ATF-4 | Modulators of UPR mitigate the pathophysiological state of ER-stress. | [246] |
Reverse misfolding of AAT | Administration of chemical chaperone: 4-phenylbutyric acid (PBA) in cell culture system and Z-AAT mice | ↓ Z-AAT secretion levels in cell culture and murine models | PBA is an important treatment of target organ injury in AAT deficiency | [247] |
Polymerization of Z-AAT | Administration of trimethylamine N-oxide (TMAO) | ↓ Conversion of the native state to a polymerogenic intermediate | TMAO control the conformational transitions of folded AAT | [248] |
Autophagy | Administration of autophagy enhancing drug carbamazepine (CBZ) in HeLa cell line HTO/Z and ATG-5–deficient cell line | ↓ Levels of ATZ insoluble and soluble fractions ↑ Autophagic flux by LC3-I and LC3-II ↓ Levels of soluble and insoluble ATZ in ATG-5 deficient line | CBZ is efficient in AAT deficiency as autophagy enhancer. | [110] |
Autophagy | Activation of ATF6 by expression of spliced ATF6 (1–373 exons) | ↑ ER-associated degradation of Z-AAT ↓ Hepatocyte loss | ATF6 pathway limits Z-AAT cell toxicity | [251] |
Autophagy | Cell lines (mouse embryonic fibroblast) with deletion in ATG-5 gene | ↓ Degradation of Z-AAT ↑ Z-AAT inclusions | Autophagic degradation prevent toxic accumulation of Z-AAT. | [235] |
Autophagy | Effect of rapamycin on mouse model of Z-AAT | ↑ Autophagic activity by number of vacuoles ↓ Intrahepatic accumulation of Z-AAT ↓ Caspase 12 levels ↓ Hepatic fibrosis | Rapamycin reduces polymerized Z-AAT and progression of liver injury. | [236] |
Autophagy | Liver-directed gene transfer of transcription factor EB (TFEB) in a mouse model of SERPINA1 deficiency. | ↓ Expression of SERPINA1 monomer ↑ Degradation of SERPINA1 polymer by autolysosomes ↓ Apoptosis and fibrosis 236 | TFEB gene transfer is a novel strategy for liver disease in SERPINA1 deficiency and prevent accumulation of toxic proteins. | [237] |
7.3. Proteolytic Pathways Induction as Potential Treatment for FG Aggregation in HHHS
7.4. Future Research through a Simplified Approach
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Protein/Disease | α-Syn/PD | AAT/AATD | FG/HHHS |
---|---|---|---|
Native Structure | 15 kDa Monomer N-terminal alpha-helix region, a central domain or NAC region and A C-terminal acidic tail | 52 kDa Monomer Nine alpha-helices, two β-sheets and a reactive center loop | 340 kDa triple fibrinogen Aα, Bβ, and γ chains Two lateral globular parts containing the C-terminus of Bβ and γ chains, a central nodule, containing the N-terminus of all chains |
Polymerization steps | Monomer → dimer → oligomer → fibrils | Monomer → Dimer → Oligomer → Inclusion | Monomer → Oligomer → Protofibril → Fibril |
Amyloid structure | Amyloid β-sheets in oligomers and fibrils | Amyloid β-sheets in dimers and oligomers | Amyloid fibril protein fibrinogen Aα |
Inclusion bodies | LBs with more than 90 protein components | Inclusions with dense material and a clear halo in the periphery | Type I: Polygonal shape Type II: Ground glass appearance Type III: Eosinophilic globules, granular structures in the periphery |
Inclusion proteins | α-syn, Tau protein, ubiquitin, neurofilament protein, β amyloid, among others | AAT M-Z and ZZ alleles | Mutated fibrinogen γ-chain |
Organelles affected in the cell | α-syn aggregates can be found in all organelles | Only present in the ER | Only present in the ER |
ER Stress response | UPR Chaperone activation PERK-dependent pathway | IL-6 and IL-8 protein production. Possible UPR activation. ER overload pathway | No available data |
Organs affected | Across the brain tissue | Liver and lungs | Liver and lungs |
Onset of disease | Chronic: Duplication/Triplication of SNCA: Symptoms from the age of 40 Idiopathic: From the age of 55 | Chronic: Symptoms from early childhood | Chronic: Symptoms from early childhood or adulthood |
Hereditary Hypofibrinogenemia with Hepatic Storage | ||||
---|---|---|---|---|
Target | Strategy | Results * | Conclusions | Ref. |
Autophagy | Expression of mutant γD domain of fibrinogen in yeast model | ↑ Clearance of FG in ER by autophagy system | Aggregates of FG are cleared from the ER via the autophagic pathway. | [126] |
Autophagy | Response to carbamazepine (CBZ) in patients with Fibrinogen storage disease (FSD). | ↑ Autophagic activity by number of autophagocytic vacuoles ↓ Levels of alanine aminotransferase ↓ Caspase and cytokeratin fragments (M30 and M65). | CBZ enhanced autophagy and reduce aggregate-related toxicity in FSD | [138] |
Proteolytic pathway | Treatment with ursodeoxycholic acid and α-tocopherol in children-patients with aguadilla HFSD | ↓ Aspartate aminotransferase ↓ Alanine aminotransferase ↓ Serum bile acids ↓ Liver damage and fibrosis | This treatment has been proposed in children with HFSD and evidence of liver damage | [257] |
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Padilla-Godínez, F.J.; Ramos-Acevedo, R.; Martínez-Becerril, H.A.; Bernal-Conde, L.D.; Garrido-Figueroa, J.F.; Hiriart, M.; Hernández-López, A.; Argüero-Sánchez, R.; Callea, F.; Guerra-Crespo, M. Protein Misfolding and Aggregation: The Relatedness between Parkinson’s Disease and Hepatic Endoplasmic Reticulum Storage Disorders. Int. J. Mol. Sci. 2021, 22, 12467. https://doi.org/10.3390/ijms222212467
Padilla-Godínez FJ, Ramos-Acevedo R, Martínez-Becerril HA, Bernal-Conde LD, Garrido-Figueroa JF, Hiriart M, Hernández-López A, Argüero-Sánchez R, Callea F, Guerra-Crespo M. Protein Misfolding and Aggregation: The Relatedness between Parkinson’s Disease and Hepatic Endoplasmic Reticulum Storage Disorders. International Journal of Molecular Sciences. 2021; 22(22):12467. https://doi.org/10.3390/ijms222212467
Chicago/Turabian StylePadilla-Godínez, Francisco J., Rodrigo Ramos-Acevedo, Hilda Angélica Martínez-Becerril, Luis D. Bernal-Conde, Jerónimo F. Garrido-Figueroa, Marcia Hiriart, Adriana Hernández-López, Rubén Argüero-Sánchez, Francesco Callea, and Magdalena Guerra-Crespo. 2021. "Protein Misfolding and Aggregation: The Relatedness between Parkinson’s Disease and Hepatic Endoplasmic Reticulum Storage Disorders" International Journal of Molecular Sciences 22, no. 22: 12467. https://doi.org/10.3390/ijms222212467