Upcoming project: Investigating The Molecular Mechanisms of SCA2 Using 3D Cerebellar Organoids and Multi-Omics Approaches: A Platform for Advancing Ataxia Research
Principal applicants: Prof Jorgen Erik Nielsen, Senior Researcher Patrick Ejlerskov and Post doc Emil Elbaek Henriksen, Rigshospitalet, Copenhagen University Hospital (Denmark)
Scientific summary:
This project aims to elucidate the molecular mechanisms underlying spinocerebellar ataxia type 2 (SCA2) by leveraging advanced 3D cerebellar organoids derived from patient-specific induced pluripotent stem cells (iPSCs). These organoids provide a physiologically relevant model to study SCA2 pathogenesis in cerebellar neurons, overcoming the limitations of traditional 2D cultures and the inaccessibility of living human cerebellar tissue. Building on preliminary findings that polyglutamine (polyQ) expansions in ataxin-2 (ATXN2) shift its interactome toward protein binding at the expense of RNA associations, the project will apply multi-omics approaches -integrating proteomics, transcriptomics, and interactionomics – to map how polyQ length variations affect ATXN2’s molecular interactions and the broader cellular environment.
The objectives include characterising the ATXN2 interactome, mapping proteomic and transcriptomic alterations, and establishing a comprehensive multi-omics platform for SCA2 research. This work will generate a robust dataset to identify disease-specific molecular changes and potential therapeutic targets, providing a foundation for future studies and advancing the understanding of SCA2 and related neurodegenerative disorders.
Lay summary:
This research project aims to enhance our understanding of spinocerebellar ataxia type 2 (SCA2), a rare neurological disorder that impairs movement coordination and balance, significantly affecting a person’s quality of life. SCA2 is caused by a specific genetic change, but the precise mechanisms by which this change leads to brain cell degeneration remain unclear.
To investigate this genetic form of ataxia, the researchers are using 3D brain tissue models called cerebellar organoids. These organoids are developed from skin cells of SCA2 patients, which are reprogrammed into stem cells and then turned into brain-like tissue. This method provides a unique opportunity to study affected brain cells without the need for invasive procedures to obtain brain tissue samples from patients, allowing the researchers to see early changes in brain cells long before symptoms appear, something impossible to study in living patients.
The primary objective is to create a comprehensive profile of the cellular processes occurring within these brain cells. They will examine protein interactions with other proteins and RNA, protein expression, gene activity patterns, and how these factors are altered in brain cells affected by SCA2. By comparing organoids derived from individuals with and without SCA2, they aim to identify crucial differences that may elucidate the underlying mechanisms of the disorder.
While immediate cures are not the expected outcome of this study, it establishes a vital foundation for future investigations that could significantly improve the prognosis and treatment options for individuals affected by SCA2 and related neurological disorders. This research will provide an unprecedented window into the cellular mechanisms of SCA2 by
using advanced 3D brain models that closely mimic the disease environment. By understanding the changes occurring in SCA2, the project may reveal new targets for diagnosis and treatment. The resulting data will serve as a platform for future studies, advancing understanding of SCA2 and potentially benefiting research into related neurological disorders, ultimately bringing us closer to improving the lives of people with ataxia.
This project is due to begin on January 1st 2026.
