ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons. ALS often overlaps clinically and pathologically with frontotemporal dementia (FTD), the second most common form of dementia. Like many neurodegenerative disorders, both ALS and FTD share a crucial pathological hallmark, the aggregation of misfolded proteins into insoluble inclusions in degenerating neurons. This process is referred to as proteinopathy. This review focuses on the proteinopathies associated with ALS, including aggregates of TDP-43, SOD1, FUS, and CHCHD10, which disrupt critical cellular processes such as RNA metabolism, mitochondrial function, and protein homeostasis. The review highlights to the identification of new types of mitochondrial and cytosolic aggregates linked to CHCHD10 -related ALS. Although the precise pathological mechanisms remain to be fully elucidated, strategies aimed at restoring proteostasis and reducing protein aggregation may be promising therapeutic approaches for treating ALS, as they directly target fundamental pathogenic mechanisms. • ALS is a fatal motor neuron disorder due to degeneration of upper and lower motor neurons. • A pathological hallmark of ALS is the aggregation of misfolded proteins into insoluble inclusions in degenerating neurons. • TDP-43 proteinopathy is a central pathological mechanism in ALS. • New types of mitochondrial and cytosolic aggregates are linked to CHCHD10 -related ALS.