gms | German Medical Science

Introduction: Misfolded proteins, which often form intracellular inclusion bodies, are a pathological hallmark of ALS. Disruption of the functional interplay between protein degradation (autophagy) and RNA processing has recently been proposed as an integrated model merging several ALS-associated genes into a common pathophysiological pathway. The E102Q mutation in Sigma receptor 1 (SigR1) causes juvenile ALS and frontotemporal lobar degeneration, but with a poorly described molecular mechanism of pathogenesis. We have previously shown that loss of SigR1 in neuronal cells impairs autophagy (Prause/Goswami et al., 2013, Vollrath et al., 2014). Here, we aimed at deciphering the molecular mechanism (s) underlying the neurotoxicity of E102Q-SigR1.

Methods, Results: E102Q-SigR1 was found to rapidly aggregate in the ER of cultured cells, leading to structural alterations of ER and mitochondria and to defects in energy metabolism and calcium homeostasis. Defective ER and proteotoxic stress generated by E102Q-SigR1 aggregates was associated with endo-lysosomal pathway impairment and dysregulation of RNA binding proteins (Matrin-3, TDP-43) (Figure 1 [Fig. 1], Figure 2 [Fig. 2]). Consistent with these findings, lumbar α-motoneurons of sALS as well as fALS patients showed increased nuclear Matrin-3 immunoreactivity and occasional cytoplasmic Matrin-3 aggregates, which were not co-localized with pTDP-43 aggregates. Cellular toxicity exerted byE102Q-SigR1 aggregates was further confirmed by the formation and co-aggregation of stress granules. Similar ultrastructural abnormalities of ER and mitochondria and analogous protein degradation (autophagy) and defects in several RNA binding proteins were observed in primary lymphoblasts cultures derived from E102Q-SigR1 fALS patients.

Conclusion: E102Q-SigR1-mediated ALS involves a vicious circle of altered ER functions, protein homeostasis and RNA metabolism.