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To investigate the genetic and clinical features of Chinese sporadic amyotrophic lateral sclerosis (SALS) patients with TARDBP mutations, we carried out a genetic analysis in a cohort of 391 SALS patients and explored the clinical manifestations of patients with TARDBP variants. Materials and methods: The coding region of all five coding exons of TARDBP, exons 2-6, were sequenced for mutations in 391 Chinese SALS patients. The clinical features of patients with TARDBP mutations were described and compared with cases in literatures. Results: Two missense mutations in TARDBP gene, c.1132A > G (p.N378D) and c.1147A > G (p.I383V), were detected in three cases, showing a low frequency (0.77%, 3/391) of TARDBP missense mutations in Chinese SALS patients. Based on a retrospective analysis of literatures, p.N378D mutation mainly presents a phenotype of early onset, whereas p.I383V mutation presents pure ALS or ALS alongside semantic variant primary progressive aphasia (svPPA), a type of frontotemporal dementia (FTD). Conclusions:Our results demonstrate that TARDBP mutation is a rare cause of Chinese SALS patients and expand the spectrum of phenotype. It is implied that genetic analysis of SALS patients plays a crucial role in uncovering the cause of disease, especially for cases developing early onset or alongside FTD.

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Background: Endoplasmic reticulum stress (ERS) occurred in S63del mutant CMT1B mice model, and few drugs has been studied. Mesencephalic astrocyte-derived neurotrophic factor (MANF) can inhibit ERS. This study aimed at investigating the effect of MANF on ERS of RT4-D6P2T schwannoma cells with S63del MPZ Mutation. Methods: Experimental grouping: blank control group, blank control + MANF group, lentivirus group, lentivirus + MANF group, S63del MPZ group, S63del MPZ + MANF group. CCK8 and Annexin-FITC /PI were used to detect cell proliferation and apoptosis. JC-1 was used to detect ∆Ψm. MANF, GRP78 and CHOP mRNA and protein were detected by using RT-qPCR, western blotting and immunofluorescence. ER-Tracker and mito-tracker were used to observe the morphology of endoplasmic reticulum (ER) and mitochondria. Results: Cell proliferation decreased (p < 0.001) and apoptosis increased (p < 0.001) in S63del MPZ group; cell proliferation increased (p = 0.005) and apoptosis decreased (p < 0.001) in S63del MPZ + MANF group. ∆Ψm decreased (p < 0.001), MANF, GRP78, CHOP, ATF6, P-PERK/PERK, P-IRE1/IRE1, Bax and Caspase3 increased (p < 0.001) and Bcl2 decreased (p < 0.001) in S63del MPZ group. MANF, GRP78, CHOP, ATF6, P-PERK/PERK, P-IRE1/IRE1, Bax and Caspase3 decreased (p < 0.001) and Bcl2 increased (p < 0.001) in S63del MPZ group. Conclusions: ERS occurred in RT4-D6P2T cells with S63del MPZ mutation, and MANF exerted protective effect in RT4-D6P2T cells with S63del MPZ mutation.

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