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Mutant glucocerebrosidase impairs alpha-synuclein degradation by blockade of chaperone-mediated autophagy

ABSTRACT: The most common genetic risk factors for Parkinson’s disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes Beta-glucocerebrosidase (GCase), an enzyme normally trafficked through the ER/ Golgi apparatus to the lysosomal lumen. We found that half of the GCase in lysosomes from post-mortem human GBA-PD brains was present on the lysosomal surface, and that this mislocalization depends on a pentapeptide motif in GCase used to target cytosolic protein for degradation by chaperone-mediated autophagy (CMA). Unfolded mutant GCase at the lysosomal surface inhibits CMA, causing accumulation of CMA substrates including -synuclein. Using single cell transcriptional analysis and comparative proteomics of brains from GBA-PD patients we confirmed reduced CMA activity and proteome changes comparable to those in CMA-deficient mouse brain. Loss of the MT GCase CMA motif is sufficient to rescue primary substantia nigra dopamine neurons from MT-GCase induced neuronal death. We conclude that MT GCase alleles block CMA function and produce -synuclein accumulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189202 | GEO | 2022/03/16

REPOSITORIES: GEO

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Mutant glucocerebrosidase impairs -synuclein degradation by blockade of chaperone-mediated autophagy

Project description:The most common genetic risk factors for Parkinson’s disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes -glucocerebrosidase (GCase), an enzyme that is normally trafficked from the endoplasmic reticulum and Golgi apparatus to the lysosomal lumen. We examined isolated lysosomes from anterior cingulate cortex, a region of high alpha-synuclein accumulation in GBA-PD, and found that while lysosomal GCase is entirely luminal in healthy controls, half of the lysosomal GBA-PD GCase was present on the lysosomal surface. This lysosomal mislocalization is dependent on a pentapeptide motif in GCase used for targeting of cytosolic proteins to lysosomes for degradation by chaperone-mediated autophagy (CMA), a type of autophagy inhibited by PD-related pathogenic proteins including -synuclein and LRRK2. Single cell transcriptional analysis and comparative proteomics of brains from GBA-PD patients demonstrated reduced CMA activity and overall proteome changes similar to those observed in mouse models with CMA blockage. We found that the delivery of unfolded mutant GCase to lysosomes decreased CMA due to recognition of unfolded mutant GCase to the chaperone hsc70, and the resulting complex binds the CMA receptor LAMP2A at the lysosomal surface. Unfolded mutant GCase is a poor substrate for translocation into the lysosomal lumen, and by interfering with LAMP2A multimerization, blocks the translocation and causes cytosolic accumulation of other CMA substrates including -synuclein and tau. In primary substantia nigra dopamine neurons, MT GCase led to neuronal death, while loss of the GCase CMA motif or deletion of -synuclein rescued the neurons. These results indicate how MT GCase alleles may converge with other PD proteins to block CMA function and produce -synuclein accumulation.

2022-02-03 | PXD028656 | Pride

GBA1 regulates the CLEAR network through Calcineurin and TFEB in cellular models of Parkinson´s disease

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Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [1]

2022-07-24 | GSE208781 | GEO

RNA-seq of human midbrain organoid models of Parkinson's Disease

Project description:Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that is characterized by the selective loss of midbrain dopamine (DA)-producing neurons and the formation of α-synuclein (α-syn)-containing inclusions named Lewy bodies (LBs). Here, we report that the loss of glucocerebrosidase (GCase), coupled with α-syn overexpression, result in substantial accumulation of detergent-resistant α-syn aggregates and Lewy body-like inclusions (LBLIs) in human midbrain-like organoids (hMLOs). These LBLIs exhibit a highly similar structure to PD-associated LBs, by displaying a spherically symmetric morphology with an eosinophilic core, and containing α-syn and ubiquitin. Importantly, hMLOs generated from PD patient-derived inducible pluripotent stem cells (iPSCs) harboring SNCA triplication also exhibit subsequent degeneration of DA neurons and LBLI formation upon chronic GCase inhibitor treatment. Taken together, our hMLOs harbouring two major PD risk factors (GCase deficiency and overproduced α-syn) successfully recapitulate major pathophysiological signatures of the disease, and highlight the broad utility of brain organoid technology in modeling human neurodegenerative diseases.

2021-08-13 | E-MTAB-7302 | biostudies-arrayexpress

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Project description:Heterozygous mutations in the glucocerebrosidase gene (GBA) are the strongest common genetic risk factors for Parkinson’s disease (PD) present in around 5-10% of PD patients, resulting in lower age of onset and exacerbating disease progression, including an increased risk of dementia. However, the exact mechanisms leading from dysfunction of the enzyme glucocerebrosidase (GCase) encoded by GBA to PD pathogenesis and neurodegeneration remain unclear. Applying a novel multi-part enrichment workflow we have developed, we have isolated and quantified peptides with phosphorylation, cysteine-modification or N-linked glycosylation simultaneously. We applied this methodology to iPSC-derived dopaminergic neurons from GBA-N370S PD patients and healthy age-matched controls, identifying large numbers of dysregulated native and modified proteins.

2023-03-04 | PXD026691 | Pride

Proteomics analysis of lysosomes and whole cell lysates from H4 cellsLysosome, H4, glucocerebrosidase

Project description:Studies have shown that the majority of Parkinson's disease patients have at least one putative damaging variant in a lysosomal storage disorder gene (60%) and in about 10% of sporadic PD subjects, the disease is associated with mutations in GBA1, a gene coding for glucocerebrosidase, a lysosomal hydrolase. However, the precise cellular and lysosome-specific alterations upon loss of glucocerebrosidase are not established. The aim of this study is to characterize the proteome-wide changes at the cellular and lysosomal level in H4 cells upon loss of the GBA gene. Moreover, we tested if reinstating glucocerebrosidase activity by treating cells with our in-house GCase-BS (glucocerebrosidase-brain shuttle) can revert these changes, both at the cellular and lysosomal level.

2023-03-24 | PXD036361 | Pride

Unexpected consequences of combined glucocerebrosidase and acid sphingomyelinase deficiency in a model of Parkinson’s disease

Project description:Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson’s disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how the combined deficiencies of both enzymes might interact to modulate PD has yet to be explored. Therefore, we created a double-knockout (DKO) AQ4 zebrafish line for both gba1 (or gba) ¶ and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO line compared to those for single mutants

2023-04-24 | GSE229995 | GEO

Single cell analysis of iPSC-derived midbrain organoids (GBA1 mutant and controls)

Project description:Mutations in the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher´s disease, are the most frequent genetic risk factor for Parkinson’s disease (PD). Here, we employed single-cell genomic approaches in induced pluripotent stem cell (iPSC)-derived midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration.

2023-03-06 | GSE198033 | GEO

Comparative transcriptome analysis in monocyte-derived macrophages of asymptomatic GBA mutation carriers and patients with GBA-associated Parkinson’s disease

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2021-10-12 | E-MTAB-11029 | biostudies-arrayexpress

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