TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.
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.
Sreedharan
Jemeen
J
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Blair
Ian P
IP
Tripathi
Vineeta B
VB
Hu
Xun
X
Vance
Caroline
C
Rogelj
Boris
B
Ackerley
Steven
S
Durnall
Jennifer C
JC
Williams
Kelly L
KL
Buratti
Emanuele
E
Baralle
Francisco
F
de Belleroche
Jacqueline
J
Mitchell
J Douglas
JD
Leigh
P Nigel
PN
Al-Chalabi
Ammar
A
Miller
Christopher C
CC
Nicholson
Garth
G
Shaw
Christopher E
CE
D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002642:Chick Embryo; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D047108:Embryonic Development; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000502:physiology; D020125:Mutation, Missense; D009474:Neurons / Q000166:cytology / Q000502:physiology
D004268:DNA-Binding Proteins; D050505:Mutant Proteins