TY - JOUR
T1 - TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis
AU - Sreedharan, Jemeen
AU - Blair, Ian P.
AU - Tripathi, Vineeta B.
AU - Hu, Xun
AU - Vance, Caroline
AU - Rogelj, Boris
AU - Ackerley, Steven
AU - Durnall, Jennifer C.
AU - Williams, Kelly L.
AU - Buratti, Emanuele
AU - Baralle, Francisco
AU - De Belleroche, Jacqueline
AU - Mitchell, J. Douglas
AU - Leigh, P. Nigel
AU - Al-Chalabi, Ammar
AU - Miller, Christopher C.
AU - Nicholson, Garth
AU - Shaw, Christopher E.
PY - 2008/3/21
Y1 - 2008/3/21
N2 - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.
AB - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.
UR - http://www.scopus.com/inward/record.url?scp=41149180753&partnerID=8YFLogxK
U2 - 10.1126/science.1154584
DO - 10.1126/science.1154584
M3 - Article
C2 - 18309045
AN - SCOPUS:41149180753
SN - 0036-8075
VL - 319
SP - 1668
EP - 1672
JO - Science
JF - Science
IS - 5870
ER -