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Glyceraldehyde-3-Phosphate Dehydrogenase Facilitates Macroautophagic Degradation of Mutant Huntingtin Protein Aggregates

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title Glyceraldehyde-3-Phosphate Dehydrogenase Facilitates Macroautophagic Degradation of Mutant Huntingtin Protein Aggregates
 
Creator Chaudhary, Surbhi
Dhiman, Asmita
Dilawari, Rahul
Chaubey, Gaurav Kumar
Talukdar, Sharmila
Modanwal, Radheshyam
Patidar, Anil
Malhotra, Himanshu
Raje, Chaaya Iyengar
Raje, Manoj
 
Subject QR Microbiology
 
Description 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.
 
Publisher Springer
 
Date 2021-08-18
 
Type Article
PeerReviewed
 
Relation https://link.springer.com/article/10.1007/s12035-021-02532-5
http://crdd.osdd.net/open/2915/
 
Identifier Chaudhary, Surbhi and Dhiman, Asmita and Dilawari, Rahul and Chaubey, Gaurav Kumar and Talukdar, Sharmila and Modanwal, Radheshyam and Patidar, Anil and Malhotra, Himanshu and Raje, Chaaya Iyengar and Raje, Manoj (2021) Glyceraldehyde-3-Phosphate Dehydrogenase Facilitates Macroautophagic Degradation of Mutant Huntingtin Protein Aggregates. MOLECULAR NEUROBIOLOGY.