Impact of ER Stress and ER-Mitochondrial Crosstalk in Huntington’s Disease

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.

An opinion on the debatable function of brain resident immune protein, T-cell receptor beta subunit in the central nervous system

“…In this review, we propose that an aberrant elevation in the expression of TCR-β subunits may be indicative of neuronal atrophy and synaptic impairments. It must be emphasized here that a substantial experimental evidence is still needed to determine whether under normal basal conditions TCR-β solely participates in synaptic transmission or does aging or a neuropathological insult aberrantly enhances TCR-β expression to facilitate neuronal loss as observed across a spectrum of neurodegenerative diseases including Huntington’s disease (HD; Cherubini et al, 2020 ; Costa and Scorrano, 2012 ; Islam, 2017 ; Maity et al, 2022 ; Paul and Snyder, 2019 ).

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“…Under basal conditions, PirB receptors do not present protein oligomers formed in neurological disorders like Alzheimer’s, disease (AD; Djurisic et al, 2013 ; Kim et al, 2013 ). However, increased mitochondrial dysfunction, oxidative stress, neuroinflammation, excitotoxicity and endoplasmic reticulum stress (ER-stress) as observed under a myriad of neuropathological conditions including HD may increase the surface expression of TCR-β subunits (Brouillet, 2014; Cherubini et al, 2020 ; Costa and Scorrano, 2012 ; Islam, 2017 ; Maity et al, 2022 ; Paul and Snyder, 2019 ). In HD, mutant huntingtin protein aggregates (mHtt) lead to an increase in ER stress and enhance Fyn kinase activity ( Maity et al, 2022 , Guglietti et al, 2021 , Tang et al, 2020 ).…”

“…However, increased mitochondrial dysfunction, oxidative stress, neuroinflammation, excitotoxicity and endoplasmic reticulum stress (ER-stress) as observed under a myriad of neuropathological conditions including HD may increase the surface expression of TCR-β subunits (Brouillet, 2014; Cherubini et al, 2020 ; Costa and Scorrano, 2012 ; Islam, 2017 ; Maity et al, 2022 ; Paul and Snyder, 2019 ). In HD, mutant huntingtin protein aggregates (mHtt) lead to an increase in ER stress and enhance Fyn kinase activity ( Maity et al, 2022 , Guglietti et al, 2021 , Tang et al, 2020 ). Also, any of the neurotoxic conditions may increase the gene expression of TCR-β and decrease the function and expression of α7 nicotinic acetylcholine receptors.…”

Repaglinide Elicits a Neuroprotective Effect in Rotenone-Induced Parkinson’s Disease in Rats: Emphasis on Targeting the DREAM-ER Stress BiP/ATF6/CHOP Trajectory and Activation of Mitophagy

“…In addition, a recent review focused on the significance of molecular mitochondria–ER crosslink in PD pathogenesis, partaking in multiple pathways beholding possible therapeutic targets . Recently, ER proteostasis network was spotlighted as a novel therapeutic aim to improve the clinical prognosis of AD and HD. , This could be translated in PD, which has some similarities to AD and HD, including sharing in the neuronal loss and synaptic abnormalities.…”

BDNF and TRiC-inspired Reagents Rescue Cortical Synaptic Deficits in a Mouse Model of Huntington’s Disease

“…How failed proteostasis may be causal for the many cellular deficits characteristic of HD is a topic of intense research interest. Indeed, mHTT is known to impact gene expression, mitochondrial function, endoplasmic reticulum (ER) function, protein turnover, axonal transport, and synaptic transmission (Bennett et al, 2007; Browne, 2008; Cepeda and Levine, 2022; Guo et al, 2016; Leitman et al, 2013; Li et al, 2003; Maity et al, 2022; Santos et al, 2010; Xie et al, 2010; Yoshii and Constantine-Paton, 2010). Defining the mechanism(s) by which mHTT contributes to pathogenesis promises to contribute significantly to understanding and treating HD.…”