# Mutated sigma-1R disrupts cell homeostasis in dHMN patient cells

## TL;DR

A mutated sigma-1 receptor disrupts cell function in patients with a neurological disorder called dHMN, leading to impaired cell homeostasis and communication.

## Contribution

This study demonstrates the functional impact of a specific sigma-1R mutation (E150K) in patient-derived cells, linking it to disrupted cell homeostasis and motor neuron degeneration.

## Key findings

- Sigma-1R expression and distribution are significantly altered in patient fibroblasts.
- Patient cells show impaired Ca2+ dynamics, ER-mitochondria tethers, and mitochondrial metabolism.
- The autophago-lysosomal pathway is enhanced in cells with the E150K mutation.

## Abstract

Hereditary-Motor-Neuropathies (dHMNs) are clinically and genetically heterogeneous neurological disorders characterized by degeneration of peripheral motoneurons. We previously identified two sigma-1 receptor (Sigma-1R) variants (p.E138Q; p.E150K) in dHMN Italian patients that behave as “loss-of-function” mutations in neuroblastoma cell lines. Here, we characterize the functional effects of Sigma-1R mutation in primary fibroblasts from homozygous patients bearing the E150K mutation, and matched controls, by performing biochemical, gene expression, immunofluorescence and Ca2+ imaging analysis. Our results show that Sigma-1R expression and distribution is significantly altered in patient fibroblasts. Moreover, patient cells present a general derangement of cell homeostasis as revealed by impairment of global Ca2+ dynamics, disorganization of the ER-mitochondria tethers, enhancement of the autophago-lysosomal pathway and blunting of mitochondrial aerobic metabolism compared to controls. These findings highlight the crucial role of Sigma-1R in the maintenance of cell and protein homeostasis, inter-organelle communication and intracellular Ca2+ signalling, supporting the notion that Sigma-1R is protective for motor neuron activity and its down-regulation and/or loss-of-function, as in the case of the E150K mutation, might play the key role in the neuronal degeneration in dHMN patients.

The online version contains supplementary material available at 10.1007/s00018-025-05676-y.