FUS mutations in sporadic juvenile ALS

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Deposition of abnormal proteins constitutes a major hallmark of the neurodegenerative diseases. The appearance of abnormal protein deposits in neurons consistently precedes cell death in the same population, as best documented in the hierarchical progression of Parkinson disease1 and Alzheimer disease.2 In most instances, mutations in the corresponding gene have been identified only in a subset of those affected, usually in patients with a distinct family history. That the cytoplasm of motor neurons harbors abnormal protein deposits in amyotrophic lateral sclerosis (ALS) has been known for some time; those deposits bind ubiquitin nonspecifically, but it was only in 2006 that TDP-43 was pinpointed as an associated protein in over 90% of cases.3 TDP-43 is normally located in neuronal and glial nuclei but in ALS it appears in cytoplasmic inclusions. Importantly, mutations in the encoding gene, TARDBP , were discovered recently in familial ALS (FALS).4 Ubiquitinated inclusions of TDP-43 also were observed in neuronal and glial cytoplasm in the majority of patients with frontotemporal lobar degeneration (FTLD-U), the most common form of frontotemporal dementia. The presence of TDP-43 …