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ABSTRACT: Spinal and bulbar muscular atrophy (SBMA) impairs motor function in men and is linked to a CAG repeat mutation in the androgen receptor (AR) gene. Defects in motoneuronal retrograde axonal transport may critically mediate motor dysfunction in SBMA, but the site(s) where AR disrupts transport is unknown. We find deficits in retrograde labeling of spinal motoneurons in both a knock-in (KI) and a myogenic transgenic (TG) mouse model of SBMA. Likewise, live imaging of endosomal trafficking in sciatic nerve axons reveals disease-induced deficits in the flux and run length of retrogradely transported endosomes in both KI and TG males, demonstrating that disease triggered in muscle can impair retrograde transport of cargo in motoneuron axons, possibly via defective retrograde signaling. Supporting the idea of impaired retrograde signaling, we find that vascular endothelial growth factor treatment of diseased muscles reverses the transport/trafficking deficit. Transport velocity is also affected in KI males, suggesting a neurogenic component. These results demonstrate that androgens could act via both cell autonomous and non-cell autonomous mechanisms to disrupt axonal transport in motoneurons affected by SBMA.
Human Molecular Genetics 08/2011; 20(22):4475-90. · 7.64 Impact Factor
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ABSTRACT: Mutations in mitochondrial DNA polymerase (pol gamma) cause several progressive human diseases including Parkinson's disease, Alper's syndrome, and progressive external ophthalmoplegia. At the cellular level, disruption of pol gamma leads to depletion of mtDNA, disrupts the mitochondrial respiratory chain, and increases susceptibility to oxidative stress. Although recent studies have intensified focus on the role of mtDNA in neuronal diseases, the changes that take place in mitochondrial biogenesis and mitochondrial axonal transport when mtDNA replication is disrupted are unknown. Using high-speed confocal microscopy, electron microscopy and biochemical approaches, we report that mutations in pol gamma deplete mtDNA levels and lead to an increase in mitochondrial density in Drosophila proximal nerves and muscles, without a noticeable increase in mitochondrial fragmentation. Furthermore, there is a rise in flux of bidirectional mitochondrial axonal transport, albeit with slower kinesin-based anterograde transport. In contrast, flux of synaptic vesicle precursors was modestly decreased in pol gamma-alpha mutants. Our data indicate that disruption of mtDNA replication does not hinder mitochondrial biogenesis, increases mitochondrial axonal transport, and raises the question of whether high levels of circulating mtDNA-deficient mitochondria are beneficial or deleterious in mtDNA diseases.
PLoS ONE 01/2009; 4(11):e7874. · 4.09 Impact Factor
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ABSTRACT: Many models of axonal elongation are based on the assumption that the rate of lengthening is driven by the production of cellular materials in the soma. These models make specific predictions about transport and concentration gradients of proteins both over time and along the length of the axon. In vivo, it is well accepted that for a particular neuron the length and rate of growth are controlled by the body size and rate of growth of the animal. In terms of modeling axonal elongation this radically changes the relationships between key variables. It raises fundamental questions. For example, during in vivo lengthening is the production of material constant or does it change over time? What is the density profile of material along the nerve during in vivo elongation? Does density change over time or vary along the nerve? To answer these questions we measured the length, mitochondrial density, and estimated the half-life of mitochondria in the axons of the medial segmental nerves of 1st, 2nd, and 3rd instar Drosophila larvae. The nerves were found to linearly increase in length at an average rate of 9.24 microm h(-1) over the 96 h period of larval life. Further, mitochondrial density increases over this period at an average rate of 4.49x10(-3) (mitochondria microm(-1))h(-1). Mitochondria in the nerves had a half-life of 35.2h. To account for the distribution of the mitochondria we observe, we derived a mathematical model which suggests that cellular production of mitochondria increases quadratically over time and that a homeostatic mechanism maintains a constant density of mitochondria along the nerve. These data suggest a complex relationship between axonal length and mass production and that the neuron may have an "axonal length sensor."
Journal of Theoretical Biology 10/2008; 255(4):369-77. · 2.21 Impact Factor
