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.
Hafezparast
Majid
M
Department of Neurodegenerative Disease, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
Klocke
Rainer
R
Ruhrberg
Christiana
C
Marquardt
Andreas
A
Ahmad-Annuar
Azlina
A
Bowen
Samantha
S
Lalli
Giovanna
G
Witherden
Abi S
AS
Hummerich
Holger
H
Nicholson
Sharon
S
Morgan
P Jeffrey
PJ
Oozageer
Ravi
R
Priestley
John V
JV
Averill
Sharon
S
King
Von R
VR
Ball
Simon
S
Peters
Jo
J
Toda
Takashi
T
Yamamoto
Ayumu
A
Hiraoka
Yasushi
Y
Augustin
Martin
M
Korthaus
Dirk
D
Wattler
Sigrid
S
Wabnitz
Philipp
P
Dickneite
Carmen
C
Lampel
Stefan
S
Boehme
Florian
F
Peraus
Gisela
G
Popp
Andreas
A
Rudelius
Martina
M
Schlegel
Juergen
J
Fuchs
Helmut
H
Hrabe de Angelis
Martin
M
Schiavo
Giampietro
G
Shima
David T
DT
Russ
Andreas P
AP
Stumm
Gabriele
G
Martin
Joanne E
JE
Fisher
Elizabeth M C
EM
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