Glyceraldehyde-3-Phosphate Dehydrogenase Facilitates Macroautophagic Degradation of Mutant Huntingtin Protein Aggregates
| Autor: | Anil Patidar, Sharmila Talukdar, Chaaya Iyengar Raje, Radheshyam Modanwal, Rahul Dilawari, Asmita Dhiman, Himanshu Malhotra, Surbhi Chaudhary, Gaurav Kumar Chaubey, Manoj Raje |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Huntingtin
Mutant Neuroscience (miscellaneous) Protein aggregation Cellular and Molecular Neuroscience Neuroblastoma Protein Aggregates stomatognathic system Cell Line Tumor Huntingtin Protein Autophagy Humans RNA Small Interfering PI3K/AKT/mTOR pathway Glyceraldehyde 3-phosphate dehydrogenase biology Chemistry TOR Serine-Threonine Kinases Glyceraldehyde-3-Phosphate Dehydrogenases Cell biology HEK293 Cells Neurology Gene Knockdown Techniques biology.protein RNA Interference Ras Homolog Enriched in Brain Protein Peptides Intracellular |
| Zdroj: | Molecular neurobiology. 58(11) |
| ISSN: | 1559-1182 |
| Popis: | Protein aggregate accumulation is a pathological hallmark of several neurodegenerative disorders. Autophagy is critical for clearance of aggregate-prone proteins. In this study, we identify a novel role of the multifunctional glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in clearance of intracellular protein aggregates. Previously, it has been reported that though clearance of wild-type huntingtin protein is mediated by chaperone-mediated autophagy (CMA), however, degradation of mutant huntingtin (mHtt with numerous poly Q repeats) remains impaired by this route as mutant Htt binds with high affinity to Hsc70 and LAMP-2A. This delays delivery of misfolded protein to lysosomes and results in accumulation of intracellular aggregates which are degraded only by macroautophagy. Earlier investigations also suggest that mHtt causes inactivation of mTOR signaling, causing upregulation of autophagy. GAPDH had earlier been reported to interact with mHtt resulting in cellular toxicity. Utilizing a cell culture model of mHtt aggregates coupled with modulation of GAPDH expression, we analyzed the formation of intracellular aggregates and correlated this with autophagy induction. We observed that GAPDH knockdown cells transfected with N-terminal mutant huntingtin (103 poly Q residues) aggregate-prone protein exhibit diminished autophagy. GAPDH was found to regulate autophagy via the mTOR pathway. Significantly more and larger-sized huntingtin protein aggregates were observed in GAPDH knockdown cells compared to empty vector-transfected control cells. This correlated with the observed decrease in autophagy. Overexpression of GAPDH had a protective effect on cells resulting in a decreased load of aggregates. Our results demonstrate that GAPDH assists in the clearance of protein aggregates by autophagy induction. These findings provide a new insight in understanding the mechanism of mutant huntingtin aggregate clearance. By studying the molecular mechanism of protein aggregate clearance via GAPDH, we hope to provide a new approach in targeting and understanding several neurodegenerative disorders. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink