Abstract
Lysosomes play a critical role in maintenance of the integrity of neuronal function, and mutations in genes that contribute to lysosome formation, transport, and activity are associated with neurodegenerative disorders. Recently, the multisubunit complex, BLOC-one-related complex (BORC), has been shown to be involved in positioning lysosomes within the cytoplasm, although the consequences of altered BORC function in adult animals have not been established. We show that a spontaneous truncation mutation in the mouse Borcs7 gene, identified through whole-genome sequencing followed by genetic complementation, results in progressive axonal dystrophy with dramatic impairment of motor function. Furthermore, mice homozygous for deletion of the entire Borcs7 coding sequence die shortly after birth, and neurons cultured from these animals show impaired centrifugal transport of lysosomes. This identifies BORCS7 as a central factor in axonal transport of lysosomes and a possible target for improving disease-related disturbances in this important function.
Highlights
Because of the relatively large fraction of cytoplasmic volume distributed throughout their axonal and dendritic processes, neurons are susceptible to accumulation of cellular waste, which cannot be diluted during cell division as it is in mitotic cells
We report here the characterization of a mouse carrying a mutation resulting in expression of a truncated version of the BLOCone-related complex (BORC) subunit BORCS7 (C10orf32/diaskedin), which results in a phenotype with many similarities to human hereditary spastic paraplegia (HSP)
This reflex is commonly used as a marker of disease progression in a number of mouse models of neurodegeneration, including neurodegeneration resulting from loss of autophagy (Komatsu et al, 2006)
Summary
Because of the relatively large fraction of cytoplasmic volume distributed throughout their axonal and dendritic processes, neurons are susceptible to accumulation of cellular waste, which cannot be diluted during cell division as it is in mitotic cells. A defect in retrograde transport of lysosomes along axons has been shown to result in motor axon degeneration in mice carrying the legs at odd angles (Loa) mutation. Mice heterozygous for this mutation, which introduces a single-amino-acid mutation into the dynein heavy chain, show decreases in both dynein processivity and run lengths for lysosomes (Ori-McKenney et al, 2010). Mutations in a zebrafish ortholog of KIF5A, which encodes the neuronal kinesin heavy chain, have been shown to result in deficits in anterograde transport of mitochondria in axons followed by neurodegeneration
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