FUS‐immunoreactive inclusions are a common feature in sporadic and non‐SOD1 familial amyotrophic lateral sclerosis
Han Xiang Deng,Hong Zhai,Eileen H. Bigio,Jianhua Yan,Faisal Fecto,Kaouther Ajroud,Manjari Mishra,Senda Ajroud-Driss,Scott Heller,Robert L. Sufit,Nailah Siddique,Enrico Mugnaini,Teepu Siddique +12 more
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TLDR
The pathogenic mechanism of the mutant FUS‐mediated ALS and potential roles of FUS in non‐FUS ALS remain to be investigated.Abstract:
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. Interpretation: 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. ANN NEUROL 2010;67:739 –748read more
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Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia
Han Xiang Deng,Wenjie Chen,Seong-Tshool Hong,Seong-Tshool Hong,Kym M. Boycott,George Gorrie,George Gorrie,Nailah Siddique,Yi Yang,Faisal Fecto,Yong-Yong Shi,Hong Zhai,Hujun Jiang,Hujun Jiang,Makito Hirano,Makito Hirano,Evadnie Rampersaud,Gerard H. Jansen,Sandra Donkervoort,Eileen H. Bigio,Benjamin Rix Brooks,Kaouther Ajroud,Robert L. Sufit,Jonathan L. Haines,Enrico Mugnaini,Margaret A. Pericak-Vance,Teepu Siddique +26 more
TL;DR: Findings link abnormalities in ubiquilin 2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention.
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TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia
TL;DR: TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies because of the striking functional and structural similarities of these proteins, which imply that abnormal RNA metabolism is a pivotal event in neurodegeneration.
Journal ArticleDOI
SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.
Faisal Fecto,Jianhua Yan,S. Pavan Vemula,Erdong Liu,Yi Yang,Wenjie Chen,Jian Guo Zheng,Yong Shi,Nailah Siddique,Hasan Arrat,Sandra Donkervoort,Senda Ajroud-Driss,Robert L. Sufit,Scott Heller,Han Xiang Deng,Teepu Siddique +15 more
TL;DR: The findings provide evidence of a direct genetic role for p62 in ALS pathogenesis and suggest that regulation of protein degradation pathways may represent an important therapeutic target in motor neuron degeneration.
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Clinical diagnosis and management of amyotrophic lateral sclerosis
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Protein aggregation in amyotrophic lateral sclerosis
TL;DR: Recent advances in the understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS are discussed.
References
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Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Journal ArticleDOI
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Manuela Neumann,Deepak M. Sampathu,Linda K. Kwong,Adam C. Truax,Matthew Micsenyi,Thomas T. Chou,Jennifer Bruce,Theresa Schuck,Murray Grossman,Christopher M. Clark,Leo McCluskey,Bruce L. Miller,Eliezer Masliah,Ian R. A. Mackenzie,Howard Feldman,Wolfgang Feiden,Hans A. Kretzschmar,John Q. Trojanowski,Virginia M.-Y. Lee +18 more
TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.
Journal ArticleDOI
Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.
Mark E. Gurney,Haifeng Pu,Arlene Y. Chiu,Mauro C. Dal Canto,Cynthia Y. Polchow,Denise D. Alexander,Jan Caliendo,Afif Hentati,Young W. Kwon,Han Xiang Deng,W. Chen,Ping Zhai,Robert L. Sufit,Teepu Siddique +13 more
TL;DR: In this article, the authors found that mutations of human Cu,Zn superoxide dismutase (SOD) contribute to the pathogenesis of familial amyotrophic lateral sclerosis (ALS).
Journal ArticleDOI
TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
Jemeen Sreedharan,Ian P. Blair,Vineeta B. Tripathi,Xun Hu,Caroline Vance,Boris Rogelj,Steven Ackerley,Steven Ackerley,Jennifer C Durnall,Kelly L. Williams,Emanuele Buratti,Francisco E. Baralle,Jacqueline de Belleroche,J. Douglas Mitchell,P. Nigel Leigh,Ammar Al-Chalabi,Christopher C.J. Miller,Christopher C.J. Miller,Garth A. Nicholson,Garth A. Nicholson,Christopher Shaw +20 more
TL;DR: The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.
Journal ArticleDOI
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.
Thomas J. Kwiatkowski,D. A. Bosco,D. A. Bosco,A. L. LeClerc,A. L. LeClerc,Eric Tamrazian,Charles R. Vanderburg,Carsten Russ,Carsten Russ,A. Davis,James M. Gilchrist,E. J. Kasarskis,Theodore L. Munsat,Paul N. Valdmanis,Guy A. Rouleau,Betsy A. Hosler,Pietro Cortelli,P. J. De Jong,Yuko Yoshinaga,Jonathan L. Haines,Margaret A. Pericak-Vance,Jianhua Yan,Nicola Ticozzi,Nicola Ticozzi,Nicola Ticozzi,Teepu Siddique,Diane McKenna-Yasek,Peter C. Sapp,Peter C. Sapp,H R Horvitz,John Landers,John Landers,Robert H. Brown,Robert H. Brown +33 more
TL;DR: Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
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