Abstract
Accumulation of misfolded proteins is a common phenomenon of several neurodegenerative diseases. The misfolding of proteins due to abnormal polyglutamine (PolyQ) expansions are linked to the development of PolyQ diseases including Huntington’s disease (HD). Though the genetic basis of PolyQ repeats in HD remains prominent, the primary molecular basis mediated by PolyQ toxicity remains elusive. Accumulation of misfolded proteins in the ER or disruption of ER homeostasis causes ER stress and activates an evolutionarily conserved pathway called Unfolded protein response (UPR). Protein homeostasis disruption at organelle level involving UPR or ER stress response pathways are found to be linked to HD. Due to dynamic intricate connections between ER and mitochondria, proteins at ER-mitochondria contact sites (mitochondria associated ER membranes or MAMs) play a significant role in HD development. The current review aims at highlighting the most updated information about different UPR pathways and their involvement in HD disease progression. Moreover, the role of MAMs in HD progression has also been discussed. In the end, the review has focused on the therapeutic interventions responsible for ameliorating diseased states via modulating either ER stress response proteins or modulating the expression of ER-mitochondrial contact proteins.
Highlights
This study provided a novel molecular mechanism that supports the involvement of endoplasmic reticulum (ER) stress in Huntington’s disease (HD) pathogenesis [78]. mutant Huntingtin protein (mHTT) expressing cells are acutely sensitive to misfolded secretory proteins
ER mitochondrial signaling is significantly involved in the development of HD pathophysiology
While Unfolded protein response (UPR) pathways and ER-mitochondria crosstalk have been extensively characterized, it is still unclear why integrated stress signaling failed to cope with stress in specific cells, such as striatum neurons, during HD
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Despite its well-studied genetic route, the cellular mechanisms of the disease onset and progression are highly complex, involving several factors that lead to gain of toxicity. Initial studies showed polyglutamine inclusions could sequester numerous other proteins contributing to the loss of function phenotypes. Initial investigations suggested the toxic nature of small oligomers are their sequestering nature of other proteins necessary for transcription and protein quality control [5]. This aggregate formation is a highly complex multi-step process that depends on a range of factors such as amino acid sequences in the flanking regions of polyglutamine stretches, post-translational modifications, presence of the molecular chaperones, etc. ER stress pathway proteins could be effective in HD pathology
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
