Written by Dr Hannah Shorrock Edited by Dr. Larissa Nitschke
Pastor and colleagues identify FDA-approved small molecules that selectively reduce the toxic polyglutamine-expanded protein in SCA6.
Selectively targeting disease-causing genes without disrupting cellular functions is essential for successful therapy development. In spinocerebellar ataxia type 6 (SCA6), achieving this selectivity is particularly complicated as the disease-causing gene produces two proteins that contain an expanded polyglutamine tract. In this study, Pastor and colleagues identified several Food and Drug Administration (FDA) approved small molecules that selectively reduce the levels of one of these polyglutamine-containing proteins without affecting the levels of the other protein, which is essential for normal brain function. By using drugs already approved by the United States Food and Drug Administration to treat other diseases, referred to as FDA-approved drugs, the team hopes to reduce the time frame for pre-clinical therapy development.
SCA6 is an autosomal dominant ataxia that causes progressive impairment of movement and coordination. This is due to the dysfunction and death of brain cells, including Purkinje neurons in the cerebellum. SCA6 is caused by a CAG repeat expansion in the CACNA1A gene. CACNA1A encodes two proteins: the a1A subunit, the main pore-forming subunit of the P/Q type voltage-gated calcium ion channel, as well as a transcription factor named a1ACT.
The a1A subunit is essential for life. Its function is less affected by the presence of the expanded polyglutamine tract than that of a1ACT. The transcription factor, a1ACT, controls the expression of various genes involved in the development of Purkinje cells. Expressing a1ACT protein containing an expanded polyglutamine tract in mice causes cerebellar atrophy and ataxia. While reducing levels of the a1A subunit may have little effect on SCA6 disease but impact normal brain cell function, reducing levels of a1ACT may improve disease in SCA6. Therefore, Pastor and colleagues decided to test the hypothesis that selectively reducing levels of the a1ACT protein without affecting levels of the a1A protein may be a viable therapeutic approach for SCA6.Continue reading “Identifying FDA-approved molecules to treat SCA6”