Lysosomal proliferation and distal degeneration in motor neurons expressing the G59S mutation in the p150Glued subunit of dynactin.
An increasing number of neurodegenerative diseases are being linked to mutations in genes encoding proteins required for axonal transport and intracellular trafficking. A mutation in p150(Glued), a component of the cytoplasmic dynein/dynactin microtubule motor complex, results in the human neurodegenerative disease distal spinal and bulbar muscular atrophy (dSBMA). We have developed a transgenic mouse model of dSBMA; these mice exhibit late-onset, slowly progressive muscle weakness but do not have a shortened lifespan, consistent with the human phenotype. Examination of motor neurons from the transgenic model reveals the proliferation of enlarged tertiary lysosomes and lipofuscin granules, indicating significant alterations in the cellular degradative pathway. In addition, we observe deficits in axonal caliber and neuromuscular junction (NMJ) integrity, indicating distal degeneration of motor neurons. However, sciatic nerve ligation studies reveal that inhibition of axonal transport is not evident in this model. Together, these data suggest that mutant p150(Glued) causes neurodegeneration in the absence of significant changes in axonal transport, and therefore other functions of dynein/dynactin, such as trafficking in the degradative pathway and stabilization of the NMJ are likely to be critical in maintaining the health of motor neurons.
Chevalier-Larsen
Erica S
ES
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085, USA.
Wallace
Karen E
KE
Pennise
Cynthia R
CR
Holzbaur
Erika L F
EL
D000818:Animals; D001370:Axonal Transport; D004195:Disease Models, Animal; D000072159:Dynactin Complex; D006801:Humans; D008247:Lysosomes / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000502:physiology*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D020125:Mutation, Missense; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009469:Neuromuscular Junction; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism
C000606360:DCTN1 protein, human; C000606364:Dctn1 protein, mouse; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D021122:Protein Subunits