title: A novel mouse model with impaired dynein/dynactin function develops amyotrophic lateral sclerosis (ALS)-like features in motor neurons and improves lifespan in SOD1-ALS mice.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by progressive motor neuron degeneration and muscle paralysis. Genetic evidence from man and mouse has indicated that mutations in the dynein/dynactin motor complex are correlated with motor neuron degeneration. In this study, we have generated transgenic mice with neuron-specific expression of Bicaudal D2 N-terminus (BICD2-N) to chronically impair dynein/dynactin function. Motor neurons expressing BICD2-N showed accumulation of dynein and dynactin in the cell body, Golgi fragmentation and several signs of impaired retrograde trafficking: the appearance of giant neurofilament swellings in the proximal axon, reduced retrograde labelling by tracer injected in the muscle and delayed expression of the injury transcription factor ATF3 after axon transection. Despite these abnormalities, BICD2-N mice did not develop signs of motor neuron degeneration and motor abnormalities. Interestingly, the BICD2-N transgene increased lifespan in 'low copy' SOD1-G93A ALS transgenic mice. Our findings indicate that impaired dynein/dynactin function can explain several pathological features observed in ALS patients, but may be beneficial in some forms of ALS.
authors.affiliation: Department of Neuroscience, Erasmus MC, PO Box 2040, 3000CA Rotterdam, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Teuling
authors.forename: Vera
authors.initials: V
authors.lastname: van Dis
authors.forename: Phebe S
authors.initials: PS
authors.lastname: Wulf
authors.forename: Elize D
authors.initials: ED
authors.lastname: Haasdijk
authors.forename: Anna
authors.initials: A
authors.lastname: Akhmanova
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.forename: Dick
authors.initials: D
authors.lastname: Jaarsma
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000072159:Dynactin Complex; D004398:Dyneins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008017:Life Expectancy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013534:Survival
chemical_list: C435206:Bicd2 protein, mouse; D002352:Carrier Proteins; D000072159:Dynactin Complex; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D004398:Dyneins