Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking.
Amyotrophic lateral sclerosis (ALS), a fatal and progressive neurodegenerative disorder characterized by weakness, muscle atrophy, and spasticity, is the most common adult-onset motor neuron disease. Although the majority of ALS cases are sporadic, approximately 5-10% are familial, including those linked to mutations in SOD1 (Cu/Zn superoxide dismutase). Missense mutations in a dynactin gene (DCTN1) encoding the p150(Glued) subunit of dynactin have been linked to both familial and sporadic ALS. To determine the molecular mechanism whereby mutant dynactin p150(Glued) causes selective degeneration of motor neurons, we generated and characterized mice expressing either wild-type or mutant human dynactin p150(Glued). Neuronal expression of mutant, but not wild type, dynactin p150(Glued) causes motor neuron disease in these animals that are characterized by defects in vesicular transport in cell bodies of motor neurons, axonal swelling and axo-terminal degeneration. Importantly, we provide evidence that autophagic cell death is implicated in the pathogenesis of mutant p150(Glued) mice. This novel mouse model will be instrumental for not only clarifying disease mechanisms in ALS, but also for testing therapeutic strategies to ameliorate this devastating disease.
Laird
Fiona M
FM
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Farah
Mohamed H
MH
Ackerley
Steven
S
Hoke
Ahmet
A
Maragakis
Nicholas
N
Rothstein
Jeffrey D
JD
Griffin
John
J
Price
Donald L
DL
Martin
Lee J
LJ
Wong
Philip C
PC
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016472:Motor Neuron Disease / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D009046:Motor Neurons / Q000473:pathology / Q000648:ultrastructure; D020125:Mutation, Missense; D016900:Neurofilament Proteins / Q000378:metabolism; D016622:Silver Staining; D013116:Spinal Cord; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1