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

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 <i>CHCHD10</i>-related ALS (<i>Chchd10^S59L/+</i> mice). This study raises the question of the presence and possible involvement of these aggregates in ALS beyond <i>CHCHD10</i>-associated motor neuron disease (MND). Using immunohistofluorescence, we analyzed SLP2/PHB expression in the spinal MNs and hippocampus of two ALS mouse models: <i>Fus^ΔNLS</i> and <i>Sod1^G86R</i>. 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 <i>Fus^ΔNLS</i> mice but not in <i>Sod1^G86R</i> mice. In ALS patients, SLP2/PHB aggregation was observed in four cases, including two with <i>C9ORF72</i> mutations. Interestingly, aggregates were absent in <i>SOD1</i>-associated ALS patients. These findings suggest that SLP2/PHB aggregation is not specific to <i>CHCHD10</i> 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.