Mutations in dynein link motor neuron degeneration to defects in retrograde transport.
Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.
Department of Neurodegenerative Disease, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
Majid
M
Hafezparast
Rainer
R
Klocke
Christiana
C
Ruhrberg
Andreas
A
Marquardt
Azlina
A
Ahmad-Annuar
Samantha
S
Bowen
Giovanna
G
Lalli
Abi S
AS
Witherden
Holger
H
Hummerich
Sharon
S
Nicholson
P Jeffrey
PJ
Morgan
Ravi
R
Oozageer
John V
JV
Priestley
Sharon
S
Averill
Von R
VR
King
Simon
S
Ball
Jo
J
Peters
Takashi
T
Toda
Ayumu
A
Yamamoto
Yasushi
Y
Hiraoka
Martin
M
Augustin
Dirk
D
Korthaus
Sigrid
S
Wattler
Philipp
P
Wabnitz
Carmen
C
Dickneite
Stefan
S
Lampel
Florian
F
Boehme
Gisela
G
Peraus
Andreas
A
Popp
Martina
M
Rudelius
Juergen
J
Schlegel
Helmut
H
Fuchs
Martin
M
Hrabe de Angelis
Giampietro
G
Schiavo
David T
DT
Shima
Andreas P
AP
Russ
Gabriele
G
Stumm
Joanne E
JE
Martin
Elizabeth M C
EM
Fisher
D000818:Animals; D000870:Anterior Horn Cells / Q000473:pathology; D017209:Apoptosis; D001370:Axonal Transport; D002454:Cell Differentiation; D002465:Cell Movement; D002490:Central Nervous System / Q000196:embryology; D002874:Chromosome Mapping; D019281:Dimerization; D004398:Dyneins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D005260:Female; D005727:Ganglia, Spinal / Q000473:pathology; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D006579:Heterozygote; D006720:Homozygote; D016631:Lewy Bodies / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016472:Motor Neuron Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009046:Motor Neurons / Q000502:physiology* / Q000648:ultrastructure; D009154:Mutation; D020125:Mutation, Missense; D009410:Nerve Degeneration; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D017354:Point Mutation; D013127:Spinal Nerves / Q000254:growth & development; D013744:Tetanus Toxin / Q000378:metabolism
D010446:Peptide Fragments; D013744:Tetanus Toxin; D004398:Dyneins