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

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

PROVIDER: PRJNA781959 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16986503.fastq.gz	Fastqsanger.gz
	SRR16986504.fastq.gz	Fastqsanger.gz
	SRR16986505.fastq.gz	Fastqsanger.gz
	SRR16986506.fastq.gz	Fastqsanger.gz
	SRR16986507.fastq.gz	Fastqsanger.gz

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Mutant glucocerebrosidase impairs alpha-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 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.

2022-03-16 | GSE189202 | GEO

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

Mutant glucocerebrosidase impairs α-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 β-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 postmortem 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). MT GCase at the lysosomal surface inhibits CMA, causing accumulation of CMA substrates including α-synuclein. Single-cell transcriptional analysis and proteomics of brains from GBA-PD patients confirmed reduced CMA activity and proteome changes comparable to those in CMA-deficient mouse brain. Loss of the MT GCase CMA motif rescued primary substantia nigra dopaminergic neurons from MT GCase-induced neuronal death. We conclude that MT GBA1 alleles block CMA function and produce α-synuclein accumulation.

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Project description:RNA-targeted degradation technologies offer significant promise for treating diseases by selectively disrupting gene expression. However, a robust method to specifically, efficiently, and programmability degrade targeted RNAs in mammalian cells is still in demand. Here, we present a versatile platform, dCas13d-directed chaperone-mediated autophagy (dCasCMA), which integrates the precise targeting capabilities of dCas13/CRISPR with the degradation efficiency of chaperone-mediated autophagy (CMA) to achieve efficient degradation of specific RNAs. By combining dCas13d with a CMA-targeting motif and customizable guide RNA (gRNA), the platform allows for accurate targeting of both exogenous and endogenous RNAs in cells. Moreover, the incorporation of multiplexed gRNA expression arrays enables the simultaneous degradation of multiple RNA targets during viral pathogenesis in live cells and in vivo. Our findings emphasize the platform’s modular design, which enables flexible combinations of dCCTM components with user-defined gRNA sequences. This versatility positions it as a promising tool for developing innovative therapies for various diseases.

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Chaperone-mediated autophagy sustains muscle stem cell regenerative function

Project description:Proteostasis supports stemness and its loss correlates with the functional decline of diverse stem cell types. Here we identify that chaperone-mediated autophagy (CMA), a selective autophagy pathway, is necessary for the regenerative capacity of muscle stem cells (MuSCs) throughout life. We show that CMA is active in MuSCs, while genetic loss of CMA in MuSCs or failure of CMA in normally aged cells causes a proliferative impairment, resulting in defective skeletal muscle regeneration. Reactivation of CMA in old MuSCs boosts their proliferative capacity and improves their regenerative ability. Using comparative proteomics to identify CMA substrates, we uncovered actin cytoskeleton and glycolytic metabolism as key processes altered in aged mice and human MuSCs. Our findings reveal CMA to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in old age.

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2021-08-11 | GSE181556 | GEO

Programmable Targeted RNA Degradation via dCas13d-Directed Chaperone-Mediated Autophagy (dCasCMA)

Project description:Programmable Targeted RNA Degradation via dCas13d-Directed Chaperone-Mediated Autophagy (dCasCMA)

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Progranulin–glucocerebrosidase complex regulates tau and alpha-synuclein inclusions to alter phenotypes in tauopathy

Project description:Many neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are characterized by abnormal protein deposition and frequently show comorbid pathology. Progranulin (PGRN) is implicated not only in TDP-43 but in tau and alpha-synuclein proteinopathies. However, the underlying mechanisms are unknown. Here, we generated P301S tau transgenic mice with PGRN haploinsufficiency and loss and found that those mice exhibit exacerbated disinhibition phenotype while showing attenuated memory impairment, hippocampal atrophy, and transcriptomic changes. Remarkably, the phenotypic alteration was accompanied by an increase in tau inclusions, which are positive for alpha-synuclein, a PGRN binding partner beta-glucocerebrosidase (GCase), and its substrate glucosylceramide. GCase inhibition or PGRN deficiency enhanced tau aggregation induced by AD-derived tau seeds in neurons. In vitro, GCase and glucosylceramide promoted P301S tau aggregation. Similar co-pathology was observed in AD and FTLD-GRN patients.

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Transcriptomic data of downregulated chaperone-mediated autophagy in glioma stem cell activity.

Project description:Transcriptomic data of downregulated chaperone-mediated autophagy in glioma stem cell activity.

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