The Consequences of GBA Deficiency in the Autophagy–Lysosome System in Parkinson’s Disease Associated with GBA
Abstract
1. Introduction
2. Parkinson’s Disease and GBA
2.1. Parkinson’s Disease and the Lysosomal System
2.2. Parkinson’s Disease Associated with GBA
3. The GBA Gene Encodes the β-Glucocerebrosidase Enzyme
4. Lipid Metabolism Alterations Associated with GBA Deficiency
4.1. Sphingolipid Alterations
4.2. GBA and Lysosomal Cholesterol Metabolism
5. α-Synuclein Metabolism
5.1. α-Synuclein Protein
5.2. α-Synuclein Interaction with Lipid Membranes
5.3. Direct GBA–α-Synuclein Interaction
6. GBA Deficiency and Macroautophagy Dysfunction
6.1. Macroautophagy in Parkinson’s Disease
6.2. Macroautophagy in Parkinson’s Disease Associated with GBA
6.2.1. GBA Inhibition by Conduritol-β-Epoxide (CBE)
6.2.2. Inhibition of GBA Expression
6.2.3. GBA-Knockout Models
6.2.4. Mutant GBA Models
6.2.5. Other Pathways Related to Macroautophagy Dysfunction in PD-GBA
7. Chaperone-Mediated Autophagy Impairment Related to GBA Dysfunction
7.1. CMA Pathway
7.2. CMA in Parkinson’s Disease: CMA-Dependent Degradation of α-Synuclein
7.3. CMA in Parkinson’s Disease Associated with GBA
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Model | Sample | MA markers | Interpretation | Reference | |
---|---|---|---|---|---|
CBE | In vitro | SH-SY5Y cells and rat cortical neurons | = LC3-II = Syn | No alterations in MA nor CMA | [126] |
SH-SY5Y cells | ↑ LC3-II, p62, Syn ↓ mTORC1 | defect in the “autolysosome reformation machinery” | [127] | ||
In vivo | Mouse | ↑ LC3-II, p62 (SNpc) ↑ proteinase-K resistant agg-Syn | Impaired MA flux | [128] | |
shRNA | In vitro | Human neuroglioma (H4) + shRNA GBA | ↑ LC3-II and LAMPs | GCase depletion causes a decline in lysosomal proteolysis that affects syn homeostasis | [129] |
SK-N-SH and rat cortical neuron | ↓ LC3-II ↓ autophagic flux ↑ α-Syn | Autophagy pathway is severely compromised inhibiting MA induction via-mTORC1 | [130] | ||
SH-SY5Y cells | ↑ LC3-II, p62 | Impairment of the lysosomal function | [127] | ||
KO | In vitro | Mixed cultures of cortical neurons and astrocytes from GBA-/- mice | ↓ LC3-II, Atg5-12 ↑ p62, ↑ α-Syn aggregated | Autophagy pathway is severely compromised | [131] |
HEK293 GBA-KO | ↑ MA markers (LAMP-2, LC3B, p62, Rab7) | Attributed to the accumulation of toxic GlcSph | [81] | ||
Immortalized neurons | ↑ LC3-II hyperactivated mTORC1 | Altered lysosomes and autophagy, decrease | [82] | ||
BE(2)M17 GBA-KO cells | = LC3-II, p62 ↓ Flux | MA is affected very lightly | [73] | ||
In vivo | Drosophila | ↑ LC3-II, p62 blocked MA flux | Failure in MA and lysosomal dysfunction | [132] | |
Mutant GBA | In vitro | Fibroblasts PD-GBA patients | = LC3-II | Lysosomal dysfunction but no MA alterations | [133] |
Fibroblasts from GD and GBA-PD patients | ↑ LC3-II MA flux blockade | Impaired autophagic flux | [134] | ||
Fibroblasts from PD-GBA patients | ↑ LC3-II, p62, α-Syn ↓ mTORC1 | Defect in the “autolysosome reformation machinery” | [127] | ||
Fibroblasts from N370/WT patient | ↑ LC3-II, p62 small effect on MA flux | Autophagy impairment cholesterol accumulation | [89] | ||
Fibroblasts iPD and PD-GBA patients | impaired autophagic flux | Impaired autophagic flux in PD-GBA | [135] | ||
PBMCs from PD patients | ↑ LC3-II (mRNA and protein) | MA induction probably as a compensatory mechanism of CMA impairment | [136] | ||
SH-SY5Y + GBA L444P | ↓ Mitophagy MA flux is working but in L444P is lower. | Mitophagy dysfunction and autophagy problesms | [137] | ||
Neural crest stem cell derived dopaminergic neurons | ↓ Cat D: = Cat B = LAMP-1 | GBA1 mutations lead to a lower level of cathepsin D protein and activity | [138] | ||
BE(2)M17 GBA-N370S and L444P cells | = LC3-II, p62 ↓ Flux | MA flux is slighted affected, MA induction activated to compensate lysosomal dysfunction. | [73] | ||
SH-SY5Y + GBA-WT/N370S, L444P, D409H and mouse primary neurons + WT/N370S GBA | ↑ MA flux | MA is OK and over activated to compensate CMA dysfunction. | [139] | ||
iPSC-DA | ↑ p62 | Lysosomal dysfunction | [140] | ||
iPSC-DA from GBA-PD patients (N370S/WT and L444P/WT) | ↑ LC3-II ↓ Flux | Autophagic and lysosomal defects. | [141] | ||
iPSC-DA from neuronopathic GD | ↑ LC3-II ↓ Flux ↓ TFEB expression | Lysosomal dysfunction | [142] | ||
iPSC-DA N370S | ↑ LC3-II, beclin 1, p62 | Autophagic/lysosomal perturbations. | [143] | ||
In vivo | Mouse D409V knock-in | = LC3, p62, LAMP-2 ↓ Beclin | No differences in lysosomal and MA markers except for beclin (impairment in initiation of autophagosome). | [144] | |
GBA L444P knockin mice | ↑ basal LC3-II, p62 Other markers: mTOR, beclin. | impaired basal autophagy and lysosomal degradation MA Flux blocked. mitophagy impairment | [137] | ||
Mouse D409V knock-in | = LAMP-2 | No changes in autophagy-lysosomal system | [145] | ||
Mouse D409V (+ ATP13A2) | = LAMP-2 | No changes in autophagy-lysosomal system | [146] |
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Pradas, E.; Martinez-Vicente, M. The Consequences of GBA Deficiency in the Autophagy–Lysosome System in Parkinson’s Disease Associated with GBA. Cells 2023, 12, 191. https://doi.org/10.3390/cells12010191
Pradas E, Martinez-Vicente M. The Consequences of GBA Deficiency in the Autophagy–Lysosome System in Parkinson’s Disease Associated with GBA. Cells. 2023; 12(1):191. https://doi.org/10.3390/cells12010191
Chicago/Turabian StylePradas, Eddie, and Marta Martinez-Vicente. 2023. "The Consequences of GBA Deficiency in the Autophagy–Lysosome System in Parkinson’s Disease Associated with GBA" Cells 12, no. 1: 191. https://doi.org/10.3390/cells12010191
APA StylePradas, E., & Martinez-Vicente, M. (2023). The Consequences of GBA Deficiency in the Autophagy–Lysosome System in Parkinson’s Disease Associated with GBA. Cells, 12(1), 191. https://doi.org/10.3390/cells12010191