Principal Researchers: Dr Ricardo Parolin Schnekenberg, Prof Joanne Ng, Prof Selina Wray and Prof Francesco Muntoni, University College London (UK)
Scientific summary:
Cerebellar ataxias are genetically heterogeneous and clinically debilitating disorders, yet many converge on a shared cellular mechanism of dysregulated IP3R1-mediated calcium release in cerebellar neurons. This pathway is central to synaptic integration, dendritic excitability, and motor coordination.
Mutations in ITPR1, which encodes IP3R1, cause neurodegenerative and neurodevelopmental forms of ataxia such as SCA15, SCA29 and Gillespie syndrome. Other ataxia genes act upstream or downstream of IP3R1, and even diseases not genetically linked to the pathway, such as SCA1/SCA2/SCA3 and Huntington’s (HD), show IP3R1 sensitisation caused by mutant proteins. Given this convergence, identifying small molecules to normalise IP3R1-driven calcium dynamics represents a promising strategy for therapeutic development across various forms of cerebellar ataxia.
The researchers propose running high-throughput screening of drug compound libraries to identify small molecules that could be repurposed or further developed as therapeutic options for cerebellar ataxias. They will use a cell-based IP3R1-specific calcium-release assay for High-Throughput Screening (HTS) of drug compound libraries and validate any promising candidates in follow up assays in iPSC-derived 3D cerebellar organoids.
Lay summary:
In this project, the researchers plan to test thousands of existing medicines in cells in the laboratory to find those that can improve cerebellar neuronal function in ataxias caused by mutations in a gene called ITPR1, such as SCA15, SCA29 and Gillespie Syndrome. The ITPR1 gene contains the instructions for making the IP3R1 protein, a receptor that plays a key role in neuronal signalling and motor coordination.
By focusing on drugs that are already available, the team aim to speed up the path to developing therapies for these ataxias. Because the same brain pathway is disrupted in other types of ataxia and related brain disorders such as SCA1, SCA2, SCA3 and Huntington’s Disease, any successful drugs could potentially benefit many more patients.
For more support or information please contact:
Ataxia UK, 12 Broadbent Close, London, N6 5JW
Website: www.ataxia.org.uk.
Helpline: 0800 995 6037
Tel: +44 (0)20 7582 1444
Email: helpline@ataxia.org.uk.
