A Mutation in the Borcs7 Subunit of the Lysosome Regulatory BORC Complex Results in Motor Deficits and Dystrophic Axonopathy in Mice
Autor: | John N. Snouwaert, Beverly H. Koller, Damaris N Lorenzo, Fernando Pardo-Manuel de Villena, Rachel J. Church, Matthew L. Wheeler, Leigh A. Jania, Andrew Saintsing, Diane Armao, Piotr A. Mieczkowski, Sheryl S. Moy, My Trang Nguyen |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Male BORC complex Neuroaxonal Dystrophies Biology medicine.disease_cause Axonal Transport General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Mice 0302 clinical medicine Loss of Function Mutation Lysosome medicine Animals Amyotrophic lateral sclerosis Neurons Mutation Mice Inbred BALB C Lysosome-Associated Membrane Glycoproteins medicine.disease Cell biology Complementation Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Cytoplasm Axoplasmic transport Kinesin Female Lysosomes 030217 neurology & neurosurgery Locomotion |
Zdroj: | Cell reports. 24(5) |
ISSN: | 2211-1247 |
Popis: | Summary 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. |
Databáze: | OpenAIRE |
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