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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Chicago, IL 60611, USA. h-deng@northwestern.edu
Han-Xiang
HX
Deng
Hong
H
Zhai
Eileen H
EH
Bigio
Jianhua
J
Yan
Faisal
F
Fecto
Kaouther
K
Ajroud
Manjari
M
Mishra
Senda
S
Ajroud-Driss
Scott
S
Heller
Robert
R
Sufit
Nailah
N
Siddique
Enrico
E
Mugnaini
Teepu
T
Siddique
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000378:metabolism; D005192:Family Health; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D009154:Mutation; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014162:Transfection / Q000379:methods; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; D025801:Ubiquitin; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1