The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLP

Endoplasmic reticulum associated degradation is required for maintaining endoplasmic reticulum homeostasis and viability of mature Schwann cells in adults

“…We examined the histopathology of the sciatic nerve of these four groups of mice at the age of 6 weeks. In accordance with previous studies (Musner et al, 2016; Sidoli et al, 2016; Stone et al, 2020), we found that PERK inactivation in SCs alone did not change SC numbers or myelin integrity in the PNS (Figures 7, 8, 9, 10). P0 immunostaining showed that the immunoreactivity of P0 was comparable in the sciatic nerve of Double cKO mice, Sel1L cKO, PERK cKO mice, and control mice (Figure 7a–d).…”

“…Additionally, a recent study showed that deletion of Derlin-2 in SCs does not affect developmental myelination in the PNS (Volpi et al, 2019 (Huang, Hsiao, Chu, Ye, & Chen, 2013;Lilley & Ploegh, 2005); however, Sel1L is essential for the ERAD activity of the Sel1L-Hrd1 complex. Therefore, these data likely reflect that ERAD impairment in loss and demyelination in the CNS at P45, there is no evidence of SC dysfunction or death in the PNS of these mice at P45 (Stone et al, 2020). In fact, in accordance to the study, we showed here that double deletion of PERK and Sel1L did not attenuate the viability or function of SCs in the PNS at the age of 6 weeks, and that Sel1L cKO mice did not display evidence of SC dysfunction or death at the age of 10 weeks.…”

“…The dogma is that actively myelinating SCs are more sensitive to disruption of ER homeostasis than mature SCs (Clayton & Popko, 2016;Lin & Popko, 2009;Volpi et al, 2017). Although impaired UPR in SCs via double deletion of PERK and ATF6α has no effect on actively myelinating SCs during development (Stone et al, 2020). Additionally, a recent study showed that deletion of Derlin-2 in SCs does not affect developmental myelination in the PNS (Volpi et al, 2019 (Huang, Hsiao, Chu, Ye, & Chen, 2013;Lilley & Ploegh, 2005); however, Sel1L is essential for the ERAD activity of the Sel1L-Hrd1 complex.…”

“…A number of studies showed that ER stress and the UPR in SCs contributes to the development of myelin disorders in the PNS (D'Antonio et al, 2013;Pennuto et al, 2008;Sidoli et al, 2016). Conversely, a recent study reported that impaired UPR in SCs via double deletion of PERK and ATF6α does not affect their viability or function in young mice under normal conditions (Stone, Wu, Nave, & Lin, 2020). Interestingly, a study showed that deletion of Derlin-2 (an ERAD effector) in SCs compromises myelin maintenance in the PNS of naïve adult mice and exacerbates myelin abnormalities in a mouse model of Charcot-Marie-Tooth 1B (CMT1B) neuropathy (Volpi et al, 2019).…”

“…Thus, we exploited mice with PERK inactivation specifically in myelin-producing cells to determine whether Sel1L deficiency causes mature SC apoptosis by inducing ER stress. A recent study has demonstrated PERK inactivation specifically in oligodendrocytes in the CNS and SCs in the PNS in PERK loxP/loxP ; CNP/Cre mice (PERK cKO mice), which are phenotypically normal and do not display any abnormalities of myelin in the CNS and PNS(Stone et al, 2020).PERK cKO mice were crossed with Sel1L cKO mice to generate Sel1L loxP/loxP ; PERK loxP/loxP ; CNP/Cre mice (Double cKO mice), Sel1L cKO mice, PERK cKO mice, and control mice. We found that young developing Double cKO mice were asymptomatic, and that adult Double cKO mice exhibited noticeably milder neurological phenotypes than Sel1L cKO mice.…”