ALS‐related SIGMAR1 Missense Mutation Causes TDP‐43 Inclusion and Mitochondrial Injury

Abstract

The dominant missense mutation (p.E102Q) by SIGMAR1 gene mutation was discovered in the patients of juvenile amyotrophic lateral sclerosis (ALS). The sigma‐1 receptor (Sig‐1R) is a chaperone protein localizing in the mitochondrial‐associated endoplasmic reticulum (ER) membrane where regulates Ca2+ transport from ER to the mitochondria through IP3 receptor (IP3R). When Sig‐1R mutant (Sig‐1RE102Q) overexpression in neuroblastoma neuro2A cells, Sig‐1RE102Q dissociated from the IP3R and formed aggregations in the cytosol (Biochem Biophys Acta 2014;1840:3320). Mitochondrial Ca2+ transport induced by IP3R stimulation was also disturbed by Sig‐1RE102Q expression, thereby reducing mitochondrial ATP production. The Sig‐1RE102Q mutant also reduced the mitochondrial membrane potential and promoted mitophagy. Moreover, the ATP reduction caused the decreased proteasome activity and in turn TAR DNA binding protein (TDP‐43) accumulation in the cytosol. These events were recapitulated by pharmacological inhibition of either proteasome or mitochondrial Ca2+ transport. In particular, decreased proteasome activity and accumulation of ubiquitinated TDP‐43 in Sig‐1RE102Q‐expressing cells were markedly aggravated under ER stress such as tunicamycin treatment. Finally, the supply of mitochondrial TCA cycle substrate, methyl pyruvate, improved the Sig‐1RE102Q‐induced reduction of ATP synthesis and proteasome activity with concomitant inhibition of cytoplasmic accumulation of TDP‐43. Taken together, mitochondrial injury associated with ALS caused by Sig‐1RE102Q‐is rescued by methyl pyruvate.