Table 1.

ER stress sensors and HD.

Sensor Proteins	Functions of Proteins during HD	References
IRE1	Inhibition of autophagy via IRE-1-TRAF2 may impair autophagic clearance of mHtt aggregates leading to neuronal degeneration.	Lee et al., 2011
	Overexpression of the ubiquitin-specific protease-14 (Usp14) reduces cellular aggregates in mutant Htt-expressing cells. Overexpression of Usp14 in turn was able to inhibit phosphorylation of IRE1α in mutant Htt-overexpressing cells and to protect against cell degeneration and caspase-3 activation.	Hyrskyluoto et al., 2014
PERK	ERK/eIF2α phosphorylation is involved in polyQ72-induced LC3 conversion, which is a prerequisite for autophagy in the expression of Huntington’s disease. It acted as a cellular defence that inhibited ER-stress-mediated cell death.	Kouroku et al., 2007
	This study proposed that use of salubrinal can reduce ER stress and counteract cell death caused by the mutant huntingtin proteins. Here increased phosphorylation of eukaryotic translation initiation factor2 subunit-α (eIF2α) by the salubrinal has shown to be neuroprotective, thereby influencing the PERK pathway.	Reijonen et al., 2008
	ERAD substrate accumulation and the related ER stress are not dependent on the presence and concentration of large visible aggregates but arise when Htt is in a monomeric or oligomeric state. Eventually all the three UPR sensors are activated including PERK.	Leitman et al., 2013
	It reveals that cultured striatal cells and murine brain striatum have remarkably low levels of phosphorylation of translation initiation factor eIF2α. eIF2α phosphorylation was elevated in a striatal cell line stably expressing pathogenic huntingtin and in brain sections of Huntington’s disease model mice.	Leitman et al., 2014
	PromISR-6 is a potent GBZ analogue, has the capability to prolong the phosphorylation time of eIF2α and protein translation inhibition, reducing mutant Htt aggregates and increasing survival in an HD cellular model, apparently by activating autophagy	Sundaram et al., 2019
	Ganz et al. developed a potent small molecule PERK activator MK-28, which showed improvement in cellular and mice models of HD. It rescued cells from undergoing ER-stress induced apoptosis. Also, it significantly improved motor and executive functions and delayed death onset in the HD induced mice model.	Ganz et al., 2020
	The level of eIF2α phosphorylation is significantly lower in the striatal cells. Interestingly, the presence of pathogenic mtHtt increased the eIF2 alpha phosphorylation in STHdh Q111/111 cells and in the murine striatum	Ma et al., 2020
ATF6	ATF6α has also been demonstrated to mediate Rheb expression, and both proteins cooperate to maintain the survival of postmitotic neurons. The ATF6α/Rheb pathway is altered in Huntington’s disease as the decrease in ATF6αprocessing is accompanied by a decrease in the accumulation of Rheb. These alterations correlate with the aberrant accumulation of cell cycle re-entry markers in post-mitotic neurons which is accompanied by death of a subset of neurons. It also leads to, compromised execution of the ER-stress response which may contribute to the pathogenesis of HD.	Fernandez et al., 2011
	They have studied the effect of TD-induced neurodegeneration and seen that ER stress markers, such as GRP78, XBP-1, CHOP, ATF-6, phosphorylated eIF2α, and cleaved caspase-12 have increased rapidly.	Wang X et al., 2020