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 postmortem tissue from SCA6 patients. Here, we show that levels of cerebellar BDNF and its receptor, tropomyosin receptor kinase B (TrkB), are reduced at an early disease stage in a mouse model of SCA6 (SCA684Q/84Q). One month of exercise elevated cerebellar BDNF expression and improved ataxia and cerebellar Purkinje cell firing rate deficits. A TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), likewise improved motor coordination and Purkinje cell firing rate and elevated downstream Akt signaling. Prolonged 7,8-DHF administration persistently improved 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.

The authors review the timelines, and probabilities, of recent vaccines progressing from phase 2 clinical trials to licensure within 10 years.

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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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