# SLP2/PHB Aggregates in ALS Mouse Models and Patients: Implications Beyond CHCHD10-Associated Motor Neuron Disease

## TL;DR

This study shows that SLP2/PHB aggregates appear in multiple forms of ALS, suggesting they may play a broader role in disease progression.

## Contribution

The study expands the relevance of SLP2/PHB aggregates beyond CHCHD10-related ALS to other subtypes.

## Key findings

- SLP2/PHB aggregates were found in FusΔNLS mice and some ALS patients, including those with C9ORF72 mutations.
- Aggregates were absent in Sod1G86R mice and SOD1-associated ALS patients.
- The presence of SLP2/PHB aggregates suggests a potential role in ALS pathogenesis across different genetic backgrounds.

## Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron (MN) degeneration, frequently overlapping with frontotemporal dementia (FTD). Protein aggregation is a hallmark of these disorders, yet the role of aggregates in ALS pathogenesis remains unclear. Previously, stomatin-like protein 2 (SLP2) and prohibitin (PHB) aggregates were identified in a model of CHCHD10-related ALS (Chchd10S59L/+ mice). This study raises the question of the presence and possible involvement of these aggregates in ALS beyond CHCHD10-associated motor neuron disease (MND). Using immunohistofluorescence, we analyzed SLP2/PHB expression in the spinal MNs and hippocampus of two ALS mouse models: FusΔNLS and Sod1G86R. Additionally, post-mortem spinal cord tissues from 27 ALS and ALS-FTD patients were analyzed. SLP2/PHB aggregates were identified in spinal MNs and the hippocampus of FusΔNLS mice but not in Sod1G86R mice. In ALS patients, SLP2/PHB aggregation was observed in four cases, including two with C9ORF72 mutations. Interestingly, aggregates were absent in SOD1-associated ALS patients. These findings suggest that SLP2/PHB aggregation is not specific to CHCHD10 variants but may contribute to the pathogenesis of ALS from different origins. The age-related accumulation of these aggregates highlights their potential role in disease progression and as therapeutic targets. Future studies should investigate their mechanistic contributions across different ALS subtypes.