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bioRxiv · 10.1101/2021.02.21.432180

Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6

Cook, A. A.·Jayabal, S.·Sheng, J.·Fields, E.·Leung, T. C. S.·Quilez, S.·McNicholas, E.·Lau, L.·Watt, A. J.
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Abstract

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease resulting in motor coordination deficits and cerebellar pathology. Expression of brain-derived neurotrophic factor (BDNF) is reduced in several neurodegenerative diseases, including in post-mortem tissue from SCA6 patients. Here, we show that cerebellar BDNF levels are reduced at an early disease stage in a mouse model of SCA6 (SCA684Q/84Q). One month of voluntary exercise was sufficient to elevate BDNF expression, as well as rescue both motor coordination and cerebellar Purkinje cell firing rate deficits. A BDNF mimetic, 7,8-dihydroxyflavone (7,8-DHF) likewise improved motor coordination and reversed Purkinje cell firing rate deficits, suggesting that exercise acts via BDNF-TrkB signaling. Prolonged chronic 7,8-DHF administration rescued ataxia when treatment commenced near disease onset, but was ineffective when treatment was started late. These data suggest that 7,8-DHF, which is orally bioavailable and crosses the blood-brain barrier, is a promising therapeutic for SCA6 and argue for the importance of early intervention for SCA6.

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Cook, A. A., Jayabal, S., Sheng, J., Fields, E., Leung, T. C. S., Quilez, S., McNicholas, E., Lau, L., Watt, A. J.. 2021-02-22. Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6. https://doi.org/10.1101/2021.02.21.432180

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