Brain Star Award winner Anna Cook

Exercise in a pill to treat a rare disease

Spinocerebellar ataxia type 6 (SCA6) is a rare inherited disease that leads to degeneration of the cerebellum, a part of the brain that coordinates movement. The disease has no cure so the identification of novel therapeutics is of high priority. Graduate student Anna Cook led a study that identified two novel therapeutic strategies for SCA6, and pinpointed pathways that were dysregulated in the disease that could lead to further treatments.

The research team found that signaling that involved the molecules brain-derived neurotrophic factor (BDNF) and its receptor, called TrkB, was disrupted in the cerebellum of SCA6 mice. They could correct this disruption with two strategies. First they used voluntary exercise to boost the levels of BDNF in the cerebellum of SCA6 mice. One month of exercise rescued motor deficits and abnormalities in the firing of the cerebellar neurons. However this strategy was limited to the earliest stages of disease, as the SCA6 mice were unable to exercise sufficiently as motor deficits progressed. Next they bypassed exercise by using 7,8-dihydroxyflavone (7,8-DHF), a molecule that mimics the action of BDNF in the brain. Like exercise, 7,8-DHF rescued motor coordination and neuron firing deficits, even when mice were less able to exercise due to the progression of motor deficits. The team also identified signaling pathways that were activated by 7,8-DHF, helping them understand how the treatment works.

Another key finding concerned the timeline of disease progression, and how therapies function across disease stages. This is important because many SCA6 patients are diagnosed long after the onset of symptoms. Although 7,8-DHF was effective for longer than exercise, neither intervention rescued deficits if it was started in the most advanced stages of disease. This underlines the importance of early diagnosis and intervention and has the potential to inform health policy.

Spinocerebellar ataxia type 6 (SCA6) is a rare disease with no cure and limited treatments. Any new treatment will be transformative for patients. Two novel therapeutic strategies for SCA6 were identified in this study: exercise and 7,8-DHF drug treatment. The impact of exercise as a treatment strategy is particularly important as it is accessible to patients worldwide even with limited healthcare access. 7,8-DHF is also a promising treatment as related molecules are currently in development for Alzheimer’s disease, which will inform clinical trials for SCA6. Alongside the discovery of two potential treatment strategies, the researchers identified other therapeutic targets, such as Akt signaling, that will lead to further research. They are already following up on these leads and expect that this will lead to further treatment discoveries.

The benefits of this research are not restricted to SCA6. BDNF and TrkB deficits have been identified in many diseases, including Huntington’s, Alzheimer’s and Parkinson’s disease, and other forms of ataxia, which together affect millions of people and have limited treatments. Thus, therapies targeting BDNF could be developed for multiple diseases.

Additionally, this publication has the potential to inform health policy concerning exercise, by providing evidence for exercise both as a general health promotion strategy and as a treatment for particular diseases. This research has also demonstrated the value of early intervention in SCA6 as both treatments worked best soon after onset. This argues for the importance of screening programs to identify affected individuals so that they can be treated as early in disease progression as possible.

About Anna Cook

Anna Cook performed this research as a PhD student in the laboratory of Dr. Alanna Watt at McGill University. Originally from the UK, she moved to Montreal to work on her favourite part of the brain – the cerebellum. In the Watt lab she has focussed her research on the rare disease spinocerebellar ataxia type 6, trying to understand what goes wrong in the cerebellum and how we can fix it.

Sources of funding

• CIHR operating grant (MOP-130570) (A.J.W.)
• CIHR project grant (PJT-153150) (A.J.W.)
• McGill Biology Doctoral Excellence Award (A.A.C.)
• Healthy Brains for Healthy Lives PhD fellowship (A.A.C. and E.F.)
• Fonds de recherche du Québec – Santé (FRQS) Doctoral Scholarship (A.A.C.)
• Returning Student award from the McGill Integrated Program in Neuroscience (S.J. x 2)
• NSERC Undergraduate Student Research Award (J.S.)
• Canada Graduate Scholarship (MSc) from CIHR (E.F.)
• Cancer Prevention and Research Institute of Texas Proteomics and Metabolomics Core Facility Support Award (RP210227) (S.H.; principal investigator, D. P. Edwards)
• NCI Cancer Center Support Grant (P30CA125123) (S.H.; principal investigator, H. Heslop), and NIH S10 award (S10OD028648) (S.H.) to Antibody-based Proteomics Core/Shared Resource (S.H.).