Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage
Abstract
:1. Introduction
2. STRING Analysis Restricted to Connections Obtained from Experimental, Gene Fusion, Protein Analogy or Proximity Data
3. Lessons from Interactions among PARK2, PARK7, PINK1, LRRK2 and VPS35
4. Lessons from Interactions between and from SYNJ1 and DNAJC6
5. Enriching the Network
6. Lessons from Transgenic Animals
Animal Model (s) | In Vivo | In Vitro | Expression Level | Main Findings | Ref. |
---|---|---|---|---|---|
Mice harbouring Sncatm1Nbm mutation (n.s.n) | X | Snca KO mice | Modulates microglial activation phenotype Increased levels of reactive marker proteins | [49] | |
Mice harbouring Sncatm1Nbm mutation (n.s.n) | X | Snca KO mice | Altered palmitate metabolism | [50] | |
Mice harbouring Sncatm1Nbm mutation (n.s.n) | X | Snca KO mice | Mitochondrial lipid abnormality Electron transport chain impairment | [51] | |
Mice harbouring Sncatm1Nbm mutation (n.s.n) | X | X | Snca KO mice | Synaptic vesicle depletion | [52] |
C57BL/6N-Sncatm1Mjff/J | X | X | Snca KO mice | Non-altered mitochondrial bioenergetics | [53] |
B6; 129 × 1-Sncatm1Rosl/J | X | Snca KO mice | α-syn restricts RNA viral infections in the brain | [54] | |
B6; 129 × 1-Sncatm1Rosl/J | X | Snca KO mice | ROS and NOS-2 decreased in mature erythrocytes | [55] | |
B6; 129 × 1-Sncatm1Rosl/J | X | Snca KO mice | No modification in pale body-like inclusion Altered proteasome function | [56] | |
B6; 129 × 1-Sncatm1Rosl/J | X | Snca KO mice | Inhibition of intrasynaptic vesicle mobility Maintains recycling-pool homeostasis | [57] | |
B6; 129 × 1-Sncatm1Rosl/J | X | Snca KO mice | Cognitive impairments | [58] | |
B6; 129 × 1-Sncatm1Rosl/J | X | Snca KO mice | Vulnerability of peripheral catecholaminergic neurons to MPTP not regulated by α-synuclein | [59] | |
B6; 129 × 1-Sncatm1Rosl/J | X | Snca KO mice | Resistant to mitochondrial toxins | [60] | |
B6; 129 × 1-Sncatm1Rosl/J | X | X | Snca KO mice | Deficits in the nigrostriatal dopamine system | [61] |
B6; 129 × 1-Sncatm1Rosl/J C57Bl/6JOlaHsd | X | X | Snca KO mice | Decreased impulsivity | [62] |
B6; 129 × 1-Sncatm1Rosl/J C57Bl/6JOlaHsd | X | Snca KO mice | Neuromuscular pathology | [63] | |
B6; 129 × 1-Sncatm1Rosl/J C57Bl/6JOlaHsd | X | X | Snca KO mice | Decreased reuptake of dopamine in the dorsal striatum | [64] |
B6; 129 × 1-Sncatm1Rosl/J (Snca KO) B6-TgHSNCGtm1VLB (Sncg KO) | X | X | -α-syn (Snca) KO mice -ɣ-syn (Sncg) KO mice | Altered dopamine metabolism | [65] |
B6; 129 × 1-Sncatm1Rosl/J (Snca KO) B6-TgHSNCGtm1VLB (Sncg KO) | X | X | -α-syn (Snca) KO mice -ɣ-syn (Sncg) KO mice -α-ɣ-syn double KO mice | Increased striatal dopamine release Hyperdopaminergic signs | [66] |
Triple-synuclein-KO (TKO) | X | X | α-syn (Snca), ß-syn (Sncb) and ɣ-syn (Sncg) triple KO mice | Functional alterations to the nigrostriatal system | [67] |
Triple-synuclein-KO (TKO) | X | X | α-syn (Snca), ß-syn (Sncb) and ɣ-syn (Sncg) triple KO mice | Altered synaptic vesicle endocytosis α -, ß -, or γ-synucleins are functionally redundant | [68] |
Triple-synuclein-KO (TKO) | X | X | α-syn (Snca), ß-syn (Sncb) and ɣ-syn (Sncg) triple KO mice | Age-dependent neuronal dysfunction | [69] |
Triple-synuclein-KO (TKO) See paper for further details on model(s) | X | X | α-syn (Snca), ß-syn (Sncb) and ɣ-syn (Sncg) triple KO mice. Mice overexpressing human SNCA mutants PARK1/hA30P or PARK4/hα-syn | Effects on presynaptic architecture | [70] |
B6;129 × 1-Sncatm1Rosl/J B6.CgTg (SNCA) OVX37Rwm Sncatm1Rosl/J | X | X | -Snca KO mice -SNCA overexpressing mice | Blockade of TrkB neurotrophic effect | [71] |
B6;DBA-Tg (Thy1-SNCA) 61Ema | X | SNCA overexpressing mice | Impairment of mitochondrial function Elevated ROS in brain mitochondria | [72] | |
B6;DBA-Tg (Thy1-SNCA) 61Ema | X | SNCA overexpressing mice | Alterations in corticostriatal synaptic plasticity | [73] | |
B6;DBA-Tg (Thy1-SNCA) 61Ema | X | X | SNCA overexpressing mice | Alterations in calcium buffering capacity | [74] |
(Thy1)-(WT)a-syn | X | SNCA overexpressing mice | Enhanced axonal degeneration after peripheral nerve lesion | [75] | |
B6.Cg-Tg (SNCA) OVX37Rwm Sncatm1Rosl/J | X | X | SNCA overexpressing mice | Deficits in dopaminergic transmission precede neuronal loss | [76] |
B6.Cg-Tg (SNCA) OVX37Rwm Sncatm1Rosl/J | X | SNCA overexpressing mice | Impairment of macroautophagy in dopaminergic neurons | [77] | |
B6; 129 × 1-Sncatm1Rosl/J neurons transfected with SNCA or TsixK-SNCA | X | Cultured neurons from Snca KO mice overexpressing SNCA or TsixK-SNCA | α-syn multimers attenuate synaptic vesicle recycling | [78] | |
S129 mutations performed on mice harbouring Sncatm1Nbm mutation (n.s.n.) | X | X | S129D-SNCA (phosphomimetic) or S129A- SNCA (non-phosphorylatable) overexpressing Snca KO mice | No abnormalities detected (in vivo) | [79] |
FVB;129S6-Sncatm1Nbm Tg (SNCA*A53T) 1Nbm Tg (SNCA*A53T) 2Nbm/J FVB;129S6-Sncatm1Nbm Tg (SNCA*A30P) 1Nbm Tg (SNCA*A30P) 2Nbm/J | X | X | A53T-SNCA or A30P-SNCA overexpressing Snca KO mice | Enteric nervous system abnormalities | [80] |
M83KO mice resulting from crossing M83 line with B6; 129X1-Sncatm1Rosl/J line | X | A30P-SNCA overexpressing Snca KO mice | Dopaminergic neurodegeneration | [81] | |
B6.Cg-Sncatm1Rosl Tg (SNCA*A30P) 192Rwm/J | X | X | A30P-SNCA overexpressing Snca KO mice | Region-specific deficits in dopamine signaling | [82] |
FVB;129-Tg (Prnp-SNCA*A53T) AAub/J | X | X | A53T-SNCA overexpressing mice | Dysfunctional neurotransmission Impaired synaptic plasticity | [83] |
FVB;129-Tg (Prnp-SNCA*A53T) AAub/J | X | X | A53T-SNCA overexpressing mice | Neuronal dysfunction in the absence of aggregate formation Behavioral alterations | [84] |
NTac:SD-Tg (SNCA*A53T) 268Cjli | X | X | A53T-SNCA overexpressing mice | Dynamic changes in striatal mGluR1 but not mGluR5 | [85] |
B6;C3-Tg (Prnp-SNCA*A53T) 83Vle/J (also known as:A53T α-synuclein transgenic line M83) | X | X | Brain inoculation with brain homogenates from older Tg mice or with human α-syn fibrils in Tg A53T-SNCA overexpressing mice | Inoculation initiates a rapidly progressive neurodegenerative α-synucleinopathy | [86] |
NTac:SD-Tg (SNCA*E46K) 70CJLi | X | X | E46K-SNCA overexpressing rats | Enhanced vulnerability to mitochondrial impairment | [87] |
Double transgenic Uchl1tm1Dgen:Thy1-maSN | X | X | Uch-L1 KO + Snca overexpressing mice | Excess α-syn worsens disease in mice lacking Uch-L1 | [88] |
B6; 129×1-Sncatm1Rosl/J C57B/6jxSJL F3, Tg5093 | X | -Snca KO mice -A53T-SNCA overexpressing mice | α-syn expression levels do not significantly affect proteasome function | [89] | |
See paper for details of the animal model(s) | X | -A53T-SNCA transfected in WT neurons -Snca KO mice | Altered fatty acid composition of dopaminergic neuron PUFAs enhance α-syn oligomerization | [90] | |
B6;129-Sncatm1Sud Sncbtm1.1Sud/J See also paper for further details | X | -Cultured neurons from Snca KO mice overexpressing SNCA -See paper for other models used | Inhibition of synaptic vesicle reclustering after endocytosis | [91] | |
B6;129×1-Sncatm1Rosl/J | X | X | α-syn fibrils gut-injected in Snca KO mice | α-syn transneuronal propagation from the gut to the brain | [92] |
WT vs. KOM2 | X | Glial cytoplasmic inclusions-α-syn or Lewy Bodies-α-syn injected in WT mice vs. mice that express human α-syn only in oligodendrocites (KOM2) | Cellular milieu affects pathology of α-syn | [93] |
Gene | Animal Model (s) | In Vivo | In Vitro | Expression Level | Main Findings | Ref. |
---|---|---|---|---|---|---|
PRKN | B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Independent regulation of parkin ubiquitination and alpha-synuclein clearance | [96] |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Accelerated microtubule aging in dopaminergic neurons | [97] | |
B6.129S4-Prkntm1Shn/J | X | Prkn KO mice | Myotubular atrophy Impaired mitochondrial function and smaller myofiber area | [98] | ||
B6.129S4-Prkntm1Shn/J | X | Prkn KO mice | Parkin mediates the ubiquitination of VPS35 Reduced WASH complexes | [99] | ||
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | ER stress and induced inflammation levels | [100] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Behavioral impairments Amplified EtOH-induced dopaminergic neurodegeneration, oxidative stress and apoptosis Dysfunction of mitochondrial autophagy | [101] | |
B6.129S4-Prkntm1Shn/J | X | Prkn KO mice | Parkin promotes proteasomal degradation of Synaptotagmin IV | [102] | ||
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | SNPH Cargo vesicle generation not affected | [103] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Exacerbated mitochondrial dysfunction in neurons | [104] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Increased sensitivity to myocardial infarction Reduced survival after the infarction Reduced mitophagy | [105] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Parkin antagonizes the death potential of FAF1 | [106] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Acutely sensitivity to oxidative stress Inability to maintain Mcl-1 levels Death of dopaminergic neurons | [107,108] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Aberrant behavioral response to dopamine replacement therapy in PD | [109] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Resisted weight gain, steatohepatitis, and insulin resistance Abolished hepatic fat uptake | [110] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Reductions in the total catecholamine release Impaired LTP and LTD Normal levels of dopamine receptors and dopamine transporters | [111] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Requiring inflammatory stimulus for nigral DA neuron loss | [112] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Reduced respiratory capacity mitochondria (in striatal cells) Delayed weight gain Lower protection against ROS | [113] | |
B6.129S4-Prkntm1Shn/J | X | X | Prkn KO mice | Increased extracellular dopamine concentration in the striatum Deficits in behavioral tests | [114] | |
Double-mutant “TwinkPark” mice, resulting from crossing B6.129S4-Prkntm1Shn/J line with Twinkledup/+ line | X | X | Prkn KO (enhanced in the substantia nigra) mice | Decrease of mitochondrial DNA Low mitochondrial function and membrane potential Neurobehavioral deficits | [115] | |
Crossing B6.129S4-Prkntm1Shn/J line with a Mcl-1 +/− line (n.s.n.) | X | X | Prkn KO + Mcl-1 +/− mice | Dopaminergic neuron loss Motor impairments | [107] | |
B6.129S4-Prkntm1Shn/J B6.129S4-Pink1tm1Shn/J | X | X | -Prkn KO mice -Pink1 KO mice | Inflammation rescued by STING-mediated action | [116] | |
B6.129S4-Prkntm1Shn/J B6.129S4-Pink1tm1Shn/J | X | X | -Prkn KO mice -Pink1 KO mice | No repression of mitochondrial antigen presentation | [117] | |
B6.129S4-Prkntm1Shn/J LEH-Pink1tm1sage | X | -Prkn KO mice -Pink1 KO rats | Mitophagy of damaged mitochondria in axons requires PINK1 and Parkin | [118] | ||
Crossing B6.129S4-Prkntm1Shn/J line and B6.129S4-Pink1tm1Shn/J line | X | Prkn/Pink1 double KO mice | Higher levels of ATP synthase Denervated neuromuscular junctions | [119] | ||
B6.129S4-Prkntm1Shn/J B6.129S4-Pink1tm1Shn/J B6.Cg-Park7tm1Shn/J | X | X | -Prkn KO mice -Pink1 KO mice -Dj-1 KO mice | Aberrant striatal synaptic plasticity in rodent models of autosomal recessive PD | [120] | |
Crossing DASYN53 double-transgenic (tetO-SNCA*A53T) E2Cai/J line + DAT-PF-tTA) mice with B6.129S4-Prkntm1Shn/J line or with Pink1tm1Zhzh mutation line (n.s.n.) | X | X | Overexpressing human A53T-SNCA in DA neurons and KO for either Prkn or Pink1 | Pervasive mitochondrial macroautophagy defects Dopamine neuron degeneration | [121] | |
B6;129-Pink1tm1Aub/J | X | Pink1 KO mice | Altered spontaneous EPSCs | [122] | ||
B6;129-Pink1tm1Aub/J | X | Pink1 KO mice | Mitochondrial recruitment of parkin not affected | [123] | ||
B6;129-Pink1tm1Aub/J | X | X | Pink1 KO mice | Progressive mitochondrial dysfunction in absence of neurodegeneration | [124] | |
LRRK2 | B6.129X1(FVB)-Lrrk2tm1.1Cai/J | X | Lrrk2 KO mice | Alterations in protein synthesis Alterations in degradation pathways | [125] | |
B6.129X1(FVB)-Lrrk2tm1.1Cai/J | X | X | Lrrk2 KO mice | LRRK2 regulates synaptogenesis and dopamine receptor activation | [126] | |
B6.129X1(FVB)-Lrrk2tm1.1Cai/J | X | Lrrk2 KO mice | LRRK2 regulates ER-Golgi export | [127] | ||
B6.129X1(FVB)-Lrrk2tm1.1Cai/J | X | Lrrk2 KO mice | Neurons have more motile axonal and dendritic growth | [128] | ||
C57BL/6-Lrrk2tm1Mjfa/J | X | X | Lrrk2 KO mice | LRRK2 modulates microglial phenotype and dopaminergic neurodegeneration | [129] | |
C57BL/6-Lrrk2tm1Mjfa/J | X | Lrrk2 KO mice | Stress-Related Gastrointestinal Dysmotility | [130] | ||
C57BL/6-Lrrk2tm1Mjfa/J | X | Lrrk2 KO mice | LRRK2 is required for Rip2 localization to DCVs | [131] | ||
C57BL/6-Lrrk2tm1Mjfa/J | X | Lrrk2 KO mice | Significant increase of ceramide levels Direct effects on GBA1 | [132] | ||
B6;129-Lrrk2tm2.1Shn/J | X | X | Lrrk2 KO mice | Impairment of Autophagy | [133] | |
B6;129-Lrrk2tm2.1Shn/J B6;129-Lrrk2tm3.1Shn/J | X | Lrrk2 KO mice | Impairment of protein degradation pathways Apoptotic cell death | [134] | ||
C57BL/6-Lrrk2tm1.1Mjff/J | X | X | Lrrk2 KO mice | No obvious bone alteration phenotypes | [135] | |
B6.Cg-Tg(Lrrk2)6Yue/J | X | X | Lrrk2 overexpressing mice | Autophagy suppression | [136] | |
B6.FVB-Tg (LRRK2) WT1Mjfa/J | X | X | LRRK2 overexpressing mice | Behavioral hypoactivity Altered dopamine-dependent short-term plasticity | [137] | |
STOCK Tg (tetO-LRRK2*G2019S) E3Cai/J | X | G2019S-LRRK2 overexpressing mice | Perturbed homeostasis Altered neuronal morphogenesis | [138] | ||
B6.Cg-Tg (Lrrk2*G2019S) 2Yue/J | X | G2019S-LRRK2 overexpressing mice | Reduction in lysosomal pH Increased expression of lysosomal ATPases | [139] | ||
B6.FVB-Tg (LRRK2*G2019S) 1Mjfa/J | X | X | G2019S-LRRK2 overexpressing mice | Synapsis gain-of-function effect of the G2019S mutation | [140] | |
NTac:SD-Tg (LRRK2*G2019S) 571CJLi | X | X | G2019S-Lrrk2 overexpressing rats | Altered bone marrow myelopoiesis Peripheral myeloid cell differentiation | [141] | |
NTac:SD-Tg (LRRK2*G2019S) 571CJLi | X | X | G2019S-Lrrk2 overexpressing rats | Enhanced α-syn gene-induced neurodegeneration | [142] | |
K-14Cre-positive Gbalnl/lnl | X | Gba KO mice (except in skin) | Reduced cerebral vascularization | [143] | ||
PINK1 | B6.129S4-Pink1tm1Shn/J | X | Pink1 KO mice | Pink1 is not required for ubiquitination of mitochondrial proteins | [144] | |
B6.129S4-Pink1tm1Shn/J | X | X | Pink1 KO mice | Reduced motor activity Slower locomotor activity time Absence of nigrostriatal dopamine loss | [145] | |
B6.129S4-Pink1tm1Shn/J | X | Pink1 KO mice | Impaired mitochondrial trafficking Fragmented mitochondria | [146] | ||
B6.129S4-Pink1tm1Shn/J | X | X | Pink1 KO mice | Hypersensitivity to MPTP-induced dopaminergic neuronal loss | [147] | |
B6.129S4-Pink1tm1Shn/J | X | Pink1 KO mice | No significant change in Ca2+ currents | [148] | ||
B6.129S4-Pink1tm1Shn/J | X | X | Pink1 KO mice | Pathological cardiac hypertrophy Greater levels of oxidative stress Impaired mitochondrial function | [149] | |
B6.129S4-Pink1tm1Shn/J | X | X | Pink1 KO mice | Impairments of corticostriatal LTP and LTD Impaired dopamine release | [150] | |
n.s.n. | X | Pink1 KO mice | Intestinal infection triggers Parkinson’s disease-like symptoms | [151] | ||
Crossing B6;129-Pink1tm1Aub/J line with dOTC line | X | X | Pink1 KO mice overexpressing OTC in DA neurons | Enhanced neurodegeneration in a model of mitochondrial stress | [152] | |
B6.129S4-Pink1tm1Shn/J B6.129S4-Prkntm1Shn/J | X | -Pink1 KO mice -Prkn KO mice | Enhanced sensitivity to group II mGlu receptor activation | [153] | ||
B6.129S4-Pink1tm1Shn/J B6.129S4-Prkntm1Shn/J | X | -Pink1 KO mice -Prkn KO mice | Reduced mitochondria functions Altered mitophagy in macrophages | [154] | ||
FVB;129-Pink1tm1Aub Tg(Prnp-SNCA*A53T)AAub/J | X | A53T-SNCA overexpressing Pink1 KO mice | Altered mitochondrial biogenesis | [155] | ||
FVB;129-Pink1tm1Aub Tg(Prnp-SNCA*A53T)AAub/J | X | X | A53T-SNCA overexpressing Pink1 KO mice | Exacerbated synucleinopathy | [156] | |
FVB;129-Pink1tm1Aub Tg(Prnp-SNCA*A53T)AAub/J | X | X | A53T-SNCA overexpressing Pink1 KO mice | Potentiation of neurotoxicity | [157] | |
Atad3afl/fl Mx1CrePink1 −/− mice, resulting from crossing B6.129S4-Pink1tm1Shn/J line with Atad3afl/fl Mx1Cre line | X | X | Pink1 KO + conditional Atad3a KO mice | Aberrant stem-cell and progenitor homeostasis Pink1-dependent mitophagy | [158] | |
B6N.129S6(Cg)-Atp13a2tm1Pjsch/J | X | X | Atp13a2 KO mice | Autophagy impairment Reduced HDAC6 activity | [159] | |
B6N.129S6(Cg)-Atp13a2tm1Pjsch/J | X | Atp13a2 KO mice | Harmful gliosis | [160] | ||
B6N.129S6(Cg)-Atp13a2tm1Pjsch/J | X | X | Atp13a2 KO mice | Neuronal ceroid lipofuscinosis Limited α-syn accumulation Sensorimotor deficits | [161] |
7. α-Synuclein: Main Character or Supporting Actor?
8. Concluding Remarks
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Inheritance | Proposed Disease Mechanism | Disease Onset | Mutation | Frequency | Confidence as Actual PD Gene | Year of Discovery | Animal Model | |
---|---|---|---|---|---|---|---|---|---|
Early | Late | ||||||||
SNCA | D | GoF or overexpression | Often with dementia | Missense or multiplication | Very rare | Very high | 1997,2003 | + | |
LRRK2 | D | GoF | X | Missense | common | Very high | 2004 | + | |
GBA | D | Likely LoF | X | Missense or LoF | common | Very high | 2009 | + | |
UCHL1 | D | LoF | NA | Missense | unclear | Low | 1998 | + | |
VPS35 | D | LoF | X | Missense | Very rare | Very high | 2011 | + | |
PRKN | R | LoF | X | Missense or LoF | rare | Very high | 1998 | + | |
PINK1 | R | LoF | X | Missense or loss of function | rare | Very high | 2004 | + | |
ATP13A2 | R | LoF | Atypical PD | Missense or LoF | Very rare | Very high | 2006 | + | |
PLA2G6 | R | LoF | X | Missense or LoF | rare | Very high | 2009 | NA | |
DNAJC6 | R | LoF | X | Missense o LoF | Very rare | High | 2012 | NA | |
SYNJ1 | R | LoF | (often) Atypical PD | Missense or loss of function | Very rare | Very high | 2013 | NA | |
DJ-1/PARK7 | R | LoF | X | Missense | Very rare | Very High | 2003 | + | |
FBXO7 | R | LoF | X | Missense | Very rare | Very High | 2008 | NA |
Gene | Ensembl Identifier | Protein | Function (Information Obtained from STRING Data Base) |
---|---|---|---|
SNCA | ENSP00000338345 | α-synuclein | Involved in regulating dopamine release and transport. Induces the fibrillization of tau protein. Reduces neuronal responsiveness to different apoptotic stimuli, thus promoting a decreased caspase-3 activation. |
LRRK2 | ENSP00000298910 | Leucine-rich repeat serine/threonine-protein kinase 2 | Regulates autophagy in a positive way by means of the calcium- dependent activation of the CaMKK/AMPK pathway, also involving the activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increases in lysosomal pH, and release of Ca++ from lysosomes. |
GBA | ENSP00000314508 | Glucosylceramidase beta | Involved in the hydrolization of glucocerebroside. Localized in lysosomes. |
UCHL1 | ENSP00000284440 | Ubiquitin carboxyl-terminal hydrolase isozyme L1 | Deubiquitinating enzyme, generates ubiquitin monomers. Might prevent the degradation of monoubiquitin in lysosomes. Its expression is highly specific to neurons and to cells of the diffuse neuroendocrine system and their tumors. |
VPS35 | ENSP00000299138 | Vacuolar protein sorting-associated protein 35 | Involved in autophagy. Is part of the retromer cargo-selective complex (CSC), which is responsible for transporting select cargo proteins between vesicular structures (e.g., endosomes, lysosomes, vacuoles) and the Golgi apparatus. |
PRKN | ENSP00000355865 | E3 ubiquitin-protein ligase parkin | Ubiquitin ligase; covalently binds ubiquitin residues onto proteins. Involved in the removal of abnormally folded or damaged proteins thanks to ‘Lys-63’-linked polyubiquitination of misfolded proteins. |
PINK1 | ENSP00000364204 | Serine/threonine-protein kinase PINK1 | Localized in mitochondria. Protects cells against stress-induced mitochondrial dysfunction by phosphorylating mitochondrial proteins. By means of activation and translocation of PRKN participates in the clearance of damaged mitochondria via selective autophagy (mitophagy). |
ATP13A2 | ENSP00000327214 | Cation-transporting ATPase 13A2 | ATPase involved in the transport of divalent transition metal cations and the maintenance of neuronal integrity. It is necessary for a correct lysosomal and mitochondrial maintenance. |
PLA2G6 | ENSP00000333142 | 85/88 kDa calcium-independent phospholipase A2 | Involved in the release of fatty acids from phospholipids. Implicated in normal phospholipid remodeling. It has also been involved in NO- or vasopressin-induced arachidonic acid release and in leukotriene and prostaglandin production. |
DNAJC6 | ENSP00000360108 | Putative tyrosine-protein phosphatase auxilin | Promotes uncoating of clathrin-coated vesicles by recruiting HSPA8/HSC70 to clathrin-coated vesicles. Involved in clathrin-mediated endocytosis in neurons. |
SYNJ1 | ENSP00000409667 | Synaptojanin-1 | Phosphoinositide phosphatase, regulates levels of membrane phosphatidylinositol-4,5-bisphosphate (PIP2). Involved in the rearrangement of actin filaments downstream of tyrosine kinase and ASH/GRB2 by means of hydrolyzing PIP2 bound to actin regulatory proteins. |
DJ-1/ PARK7 | ENSP00000418770 | Protein/nucleic acid deglycase DJ-1 | Under an oxidative condition, via its chaperone activity, inhibits the aggregation of α-synuclein, thus functioning as a redox-sensitive chaperone and as a sensor for oxidative stress. Deglycates proteins and nucleotides, and the Maillard adducts formed between amino groups of proteins or nucleotides and reactive carbonyl groups of glyoxals. |
FBXO7 | ENSP00000266087 | F-box only protein 7 | Part of a SCF (SKP1-CUL1-F- box protein) E3 ubiquitin-protein ligase complex involved in protein ubiquitination. Role in the clearance of damaged mitochondria (mitophagy). |
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Franco, R.; Rivas-Santisteban, R.; Navarro, G.; Pinna, A.; Reyes-Resina, I. Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage. Int. J. Mol. Sci. 2021, 22, 4643. https://doi.org/10.3390/ijms22094643
Franco R, Rivas-Santisteban R, Navarro G, Pinna A, Reyes-Resina I. Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage. International Journal of Molecular Sciences. 2021; 22(9):4643. https://doi.org/10.3390/ijms22094643
Chicago/Turabian StyleFranco, Rafael, Rafael Rivas-Santisteban, Gemma Navarro, Annalisa Pinna, and Irene Reyes-Resina. 2021. "Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage" International Journal of Molecular Sciences 22, no. 9: 4643. https://doi.org/10.3390/ijms22094643