Accumulation of aberrant misfolded proteins is a major hallmark of several neurodegenerative diseases. Intracellular accumulations of such abnormal proteins are selectively cleared by the ubiquitin-proteasome system (UPS). But how the failure of misfolded protein degradation cause proteinopathies is still an unanswered question?. Previous studies have suggested that few selective quality control (QC) E3 ubiquitin ligase from the UPS can selectively target insoluble aggregated proteins for their intracellular degradation. Few reports suggest that lack or aberrant functions of QC E3 ubiquitin ligases can be a possible causative factor of neurodegeneration and aging. Earlier findings indicated that leucine-rich repeat and sterile alpha motif containing-1 (LRSAM1) is associated with Charcot-Marie-Tooth Type 2P (CMT2P) disease in which loss of LRSAM1 function sensitizes peripheral axons for degeneration. Here, our current study for the first time demonstrates that E3 ubiquitin Ligase LRSAM1 is a really interesting new gene (RING) class protein which suppresses the accumulation of misfolded protein aggregates and also alleviates their deleterious cytotoxic effects. We have also observed that LRSAM1 expression is elevated under neurodegenerative stress conditions, and partial depletion of LRSAM1 endogenous levels aggravates mitochondrial abnormalities and severely affects cell survival during proteotoxic insults. Overall, our current finding indicates that LRSAM1 can alleviate cytotoxic insults mediated by a variety of neurodegeneration linked proteotoxic stress events, and most likely LRSAM1 interplay a significant role in between different components of cellular protein quality control mechanism. This study will also allow us to better comprehend the problem of proteinopathies linked with aberrant protein accumulation and open new possibilities to better elucidate the molecular mechanisms involved in the pathologies of neurodegeneration and aging.
Keywords: Cell death; Hsp70; LRSAM1; Misfolded proteins; Ubiquitin ligase.
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