Human Molecular Genetics Advance Access originally published online on March 25, 2008
Human Molecular Genetics 2008 17(13):1946-1955; doi:10.1093/hmg/ddn092
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Lysosomal proliferation and distal degeneration in motor neurons expressing the G59S mutation in the p150Glued subunit of dynactin
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
* To whom correspondence should be addressed at: University of Pennsylvania School of Medicine, D400 Richards Building, 3700 Hamilton Walk, Philadelphia, PA 19104-6085, USA. Tel: +1 2155733257; Fax: +1 2155735851; Email: holzbaur{at}mail.med.upenn.edu
Received November 30, 2007; Revised February 22, 2008; Accepted March 18, 2008
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 p150Glued, 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 p150Glued 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.
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