FUS‐immunoreactive inclusions are a common feature in sporadic and non‐SOD1 familial amyotrophic lateral sclerosis

TLDR

Amyotrophic lateral sclerosis is a fatal motor neuron disease, mostly sporadic but with 5–10 % familial cases, and recent work shows that FUS mutations underlie about 4–5 % of familial and some sporadic ALS. The study used immunostaining of postmortem spinal cords and brains from 100 ALS cases—including sporadic, familial, and dementia‑associated forms—to investigate the role of FUS in disease pathology. FUS‑immunoreactive inclusions were found in all sporadic and non‑SOD1 familial ALS cases, co‑localizing with TDP‑43, p62, and ubiquitin, and the data suggest that FUS is a common component of inclusions in these disorders, indicating a shared pathogenic pathway distinct from SOD1‑linked ALS.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration. Most cases of ALS are sporadic (SALS), but about 5 to 10% of ALS cases are familial (FALS). Recent studies have shown that mutations in FUS are causal in approximately 4 to 5% of FALS and some apparent SALS cases. The pathogenic mechanism of the mutant FUS-mediated ALS and potential roles of FUS in non-FUS ALS remain to be investigated.Immunostaining was performed on postmortem spinal cords from 78 ALS cases, including SALS (n = 52), ALS with dementia (ALS/dementia, n = 10), and FALS (n = 16). In addition, postmortem brains or spinal cords from 22 cases with or without frontotemporal lobar degeneration were also studied. In total, 100 cases were studied.FUS-immunoreactive inclusions were observed in spinal anterior horn neurons in all SALS and FALS cases, except for those with SOD1 mutations. The FUS-containing inclusions were also immunoreactive with antibodies to TDP43, p62, and ubiquitin. A fraction of tested FUS antibodies recognized FUS inclusions, and specific antigen retrieval protocol appeared to be important for detection of the skein-like FUS inclusions.Although mutations in FUS account for only a small fraction of FALS and SALS, our data suggest that FUS protein may be a common component of the cellular inclusions in non-SOD1 ALS and some other neurodegenerative conditions, implying a shared pathogenic pathway underlying SALS, non-SOD1 FALS, ALS/dementia, and related disorders. Our data also indicate that SOD1-linked ALS may have a pathogenic pathway distinct from SALS and other types of FALS.