The Role of Rab Proteins in Parkinson’s Disease Synaptopathy
Abstract
:1. Introduction
2. Rabs and Synaptic Function
3. Major Rab Alterations in PD and Other Forms of Parkinsonism: A Focus on aSyn-, GBA1- and LRRK2-Associated Synaptopathy
3.1. Rabs and aSyn-Related Synaptopathy
3.2. Critical Involvement of Rabs in LRRK2-Associated Parkinsonism
3.3. Involvement of Rabs in Other Genetic Forms of Parkinsonism
4. Interplay between Rabs and Autophagic Defects in PD Synaptopathy
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Rab Alterations and aSyn-Related Synaptopathy | ||
Rab | Alteration Type | References |
Mutations Identified in Rabs | ||
RAB39B | c.503C > A missense mutation | [92] |
RAB39B | c.557G > A missense mutation | [94] |
RAB39B | c.574G > A missense mutation | [95] |
RAB39B | c.432delA single base pair deletion | [96] |
RAB39B | c. 536dupA duplication | [97] |
RAB39B | c.543A > G; c.215 + 61G > ; c.215 + 39C > G | [98] |
RAB39B | c.137dupT; c.371delA | [99] |
Activity or pathological changes | ||
Rab3a | Loss of coupling with rabphilin | [100] |
Rab35 | Increased levels in PD patient serum | [101] |
Rab5 | Accumulation in GCI | [102,103] |
Rab1 | Increased levels protect against aSyn-mediated neuron loss | [104] |
Rab3a | Protects against aSyn-mediated neuron loss | [105] |
Rab8a | Protects against aSyn-mediated neuron loss | [105] |
Rab3a | Aberrant interaction with A30P aSyn | [107] |
Rab5 | Aberrant interaction with A30P aSyn | [107] |
Rab8 | Aberrant interaction with A30P aSyn | [107] |
Rab8b | Promotes aSyn aggregate clearance | [108] |
Rab11a | Promotes aSyn aggregate clearance/aSyn secretion | [108] |
Rab13 | Promotes aSyn aggregate clearance/aSyn secretion | [108] |
Rab3a | Regulates aSyn binding to presynaptic membranes | [109] |
Rab5a | Mediates aSyn endocytosis (spreading?) | [110] |
Rab27b | Reduces aSyn spreading via nonexosomal pathways | [111] |
Rab Alterations in LRRK2-Associated Parkinsonism | ||
Rab | Alteration Type | References |
Phosphorylation/activity changes | ||
Rab8a | Aberrant phosphorylation by G2019S-LRRK2 | [119] |
Rab7L1 | Aberrant phosphorylation by R1441C, Y1699C and G2019S-LRRK2 | [120] |
Rab10 | Phosphorylation increase (R1441C)/decrease (G2019S) | [123] |
Rab7 | Decrease in protein activity induced by expression of PD-associated LRRK2 mutants | [124] |
Rab8a | Impaired function mediated by G2019S-LRRK2 | [126] |
Rab35 | Increased phosphorylation mediated by G2019S-LRRK2 | [128] |
Rab impact on physiological and pathological LRRK2 trafficking | ||
Trafficking changes | ||
Rab29 | Abnormal recruitment of R1441G/C and Y1699C-LRRK2 to the Golgi without affecting LRRK2 phosphorylation activity | [121,122] |
Rab32 | Regulates LRRK2 late endosomal transport | [130] |
Rabs in Autophagy and Autophagy-Related Synaptic Alterations | ||
---|---|---|
Rab | ROLE | Reference |
Rab39b | Autophagy activation and fusion of autophagosomes with lysosomes | [30] |
Rab26 | Directs SVs into pre-autophagosomal structures | [90] |
Rab1 | Autophagosome formation | [163] |
Rab5 | Autophagosome formation | [163] |
Rab7 | Autophagosome formation | [163] |
Rab7 | Fusion of autophagosomes with lysosomes | [163] |
Rab8b | Autophagosome formation (non-canonical autophagy) | [163] |
Rab8b | Autophagy-based unconventional secretory pathway | [163] |
Rab9a | Autophagosome formation | [163] |
Rab11 | Amphisome formation | [163] |
Rab23 | Autophagosome formation | [163] |
Rab24 | Fusion of autophagosomes with lysosomes | [163] |
Rab32 | Autophagosome formation | [163] |
Rab33b | Autophagosome formation | [163] |
Rab7 | Involved in autophagosome formation during mitophagy | [170] |
Rab8a | Downstream target of PINK1 | [171] |
Rab8b | Downstream target of PINK1 | [166] |
Rab13 | Downstream target of PINK1 | [171] |
Rab5 | Directs SVs to autophagy | [181] |
Rab35 | Directs SVs to autophagy | [181] |
Rab4 | Autophagosome formation and maturation | [181] |
Rab5 | Autophagosome formation and maturation | [181] |
Rab10 | Autophagosome formation and maturation | [181] |
Rab11 | Autophagosome formation and maturation | [181] |
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Bellucci, A.; Longhena, F.; Spillantini, M.G. The Role of Rab Proteins in Parkinson’s Disease Synaptopathy. Biomedicines 2022, 10, 1941. https://doi.org/10.3390/biomedicines10081941
Bellucci A, Longhena F, Spillantini MG. The Role of Rab Proteins in Parkinson’s Disease Synaptopathy. Biomedicines. 2022; 10(8):1941. https://doi.org/10.3390/biomedicines10081941
Chicago/Turabian StyleBellucci, Arianna, Francesca Longhena, and Maria Grazia Spillantini. 2022. "The Role of Rab Proteins in Parkinson’s Disease Synaptopathy" Biomedicines 10, no. 8: 1941. https://doi.org/10.3390/biomedicines10081941