AI Article Synopsis
- The study investigates the effects of the N370S mutation in the GBA1 gene, linked to an increased risk for Parkinson's disease (PD), using patient-derived fibroblasts.
- Researchers examined various cellular processes, including the autophagy-lysosome pathway and endoplasmic reticulum (ER) stress, using advanced techniques like Western blotting and flow cytometry.
- Findings indicate that the N370S mutation leads to reduced β-glucocerebrosidase-1 enzyme activity, causing ER stress, dysfunctional lysosomes, cholesterol accumulation, impaired cellular removal mechanisms, and increased cell death, contributing to PD pathology.
Article Abstract
Background: Heterozygous mutations in the GBA1 gene, which encodes the lysosomal enzyme β-glucocerebrosidase-1, increase the risk of developing Parkinson's disease, although the underlying mechanisms remain unclear. The aim of this study was to explore the impact of the N370S-GBA1 mutation on cellular homeostasis and vulnerability in a patient-specific cellular model of PD.
Methods: We isolated fibroblasts from 4 PD patients carrying the N370S/wild type GBA1 mutation and 6 controls to study the autophagy-lysosome pathway, endoplasmic reticulum stress, and Golgi apparatus structure by Western blot, immunofluorescence, LysoTracker and Filipin stainings, mRNA analysis, and electron microscopy. We evaluated cell vulnerability by apoptosis, reactive oxygen species and mitochondrial membrane potential with flow cytometry.
Results: The N370S mutation produced a significant reduction in β-glucocerebrosidase-1 protein and enzyme activity and β-glucocerebrosidase-1 retention within the endoplasmic reticulum, which interrupted its traffic to the lysosome. This led to endoplasmic reticulum stress activation and triggered unfolded protein response and Golgi apparatus fragmentation. Furthermore, these alterations resulted in autophagosome and p62/SQSTM1 accumulation. This impaired autophagy was a result of dysfunctional lysosomes, indicated by multilamellar body accumulation probably caused by increased cholesterol, enlarged lysosomal mass, and reduced enzyme activity. This phenotype impaired the removal of damaged mitochondria and reactive oxygen species production and enhanced cell death.
Conclusions: Our results support a connection between the loss of β-glucocerebrosidase-1 function, cholesterol accumulation, and the disruption of cellular homeostasis in GBA1-PD. Our work reveals new insights into the cellular pathways underlying PD pathogenesis, providing evidence that GBA1-PD shares common features with lipid-storage diseases. © 2017 International Parkinson and Movement Disorder Society.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/mds.27119 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Bile acid synthesis impedes tumor-specific T cell responses during liver cancer.
Science
January 2025
NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.
The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid -acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy.
View Article and Find Full Text PDFDeveloping Topics.
Alzheimers Dement
December 2024
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
Background: Autophagy-lysosomal pathway (ALP) efficiency declines Alzheimer's disease (AD). In AD mouse models expressing a fluorescent autophagy and pH probe, autolysosomes pH elevation, resulting from deficient v-ATPase activity, causes autophagy substrates, including Aβ and APP-βCTF, to build up selectively within autolysosomes before extracellular amyloid deposits. In the most compromised but still intact neurons, massive numbers of Aβ-positive autolysosomes pack into huge petal-like blebs bulging out from the perikaryal membrane (PANTHOS).
View Article and Find Full Text PDFBackground: G protein-coupled receptors (GPCRs) are associated with multiple stages of the pathophysiology of Alzheimer's disease (AD). Biased GPCR signaling preferentially activates G protein- or β-arrestin-mediated signaling pathways and presents opportunities to develop more selective and safer therapeutics but remains largely unexplored in AD. Recently, we developed a G protein-biased GPR3 AD mouse model, which does not recruit β-arrestin 2, that displays reduced amyloid-β (Aβ) pathology without adverse cognitive effects associated with elimination of both G protein and β-arrestin signaling.
View Article and Find Full Text PDFDeveloping Topics.
Alzheimers Dement
December 2024
University of Pennsylvania, Philadelphia, PA, USA.
Background: Epidemiological studies indicate that chronic short sleep and/or disrupted sleep are all associated with metabolic dysfunction, cardiovascular risk, cognitive impairments, and increased risk for Alzheimer's disease. We have shown that acute sleep deprivation disrupts proteostasis, leading to the activation of an adaptive endoplasmic reticulum (ER) stress response known as the unfolded protein response (UPR). However, prolonged ER stress triggers the integrated stress response, which has been implicated in memory impairments.
View Article and Find Full Text PDFCaveolin-1 mitigates the advancement of metabolic dysfunction-associated steatotic liver disease by reducing endoplasmic reticulum stress and pyroptosis through the restoration of cholesterol homeostasis.
Int J Biol Sci
January 2025
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, which has the potential to advance to fibrosis. CAV1 has the effects of improving liver lipid deposition in MASLD, however, the potential mechanism is largely unknown. Here, we establish a MASLD mouse model in CAV1 knockout (KO) mice and perform transcriptome analysis on livers from mice to investigate the effects of CAV1 in MASLD progression.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!