• Han-Xiang Deng, Hong Zhai, Eileen H Bigio, Jianhua Yan, Faisal Fecto, Kaouther Ajroud, Manjari Mishra, Senda Ajroud-Driss, Scott Heller, Robert Sufit, Nailah Siddique, Enrico Mugnaini, and Teepu Siddique.
• Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Chicago, IL 60611, USA. h-deng@northwestern.edu
• Ann. Neurol. 2010 Jun 1; 67 (6): 739-48.

ObjectiveAmyotrophic 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.MethodsImmunostaining 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.ResultsFUS-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.InterpretationAlthough 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.

34 keywords...

hide…