Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration

TLDR

Mutations in the Sigma‑1 receptor (SIGMAR1) are linked to amyotrophic lateral sclerosis and its loss in mice causes locomotor deficits, yet the cellular mechanisms underlying these motor phenotypes remain unknown. The study investigates the role of SIGMAR1 in motor neuron biology. The authors used in vivo mouse models and primary motor neuron cultures to probe SIGMAR1 function. Loss of SIGMAR1 causes locomotor deficits, axonal degeneration, and motor neuron loss in mice, and in cultured motor neurons it disrupts ER–mitochondria contacts, calcium signaling, ER stress, and mitochondrial dynamics, leading to degeneration that can be prevented by rescuing calcium homeostasis or ER stress, highlighting therapeutic targets for motor neuron disease.

Abstract

Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1−/− mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum–mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases.