The Impact of Gene Fusions on ALS Disease Progression

March 10, 2024

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Understanding ALS Disease Biology to Pursue Repair and Regeneration

The Impact of Gene Fusions on ALS Disease Progression: Ghazaleh Sadri-Vakili, MD, PhD

Genetics is an important risk factor for amyotrophic lateral sclerosis (ALS) and over 50 causative or disease-modifying genes have been identified and linked to the disease. Additionally, genetic risk factors also contribute to sporadic ALS; however, the causes of more than 80% of cases are still unknown. One major potential genetic cause of ALS may be structural variants, such as deletions, duplications, insertions, inversions and translocations within the genome that had not been systematically examined. We recently used publicly available RNA-Seq datasets from Target ALS and the ALS Consortium and deployed an open-access software to identify any possible gene fusion events in ALS.

Our analysis revealed there is a significant increase in fusion genes in ALS and identified 90 rare gene fusion pairs in ALS, defined as those absent from control cases as well as from known cancer databases, given that fusion events are well-characterized in cancer. Since the causes of more than 80% of ALS cases are still unknown, the identification of ALS-specific gene fusions may improve our understanding of the mechanisms underlying motor neuron loss and identify novel potential therapeutic targets.

Additionally, there is an urgent unmet need of biomarkers for both ALS diagnosis and prognosis. In this respect, ALS-specific gene fusions may be a viable diagnostic biomarker and, once we characterize their molecular consequences, they may also serve as potential prognostic biomarker. We predict that ALS-specific gene fusions may improve many aspects of clinical care as already demonstrated in the field of oncology and are now working to understand how the fusions effect ALS disease progression.

Ghazaleh Sadri-Vakili, MS, PhD directs the NeuroEpigenetics laboratory at MassGeneral Institute for Neurodegenerative Disease, where she focuses on identifying common mechanisms that cause neurodegenerative disease to identify novel therapeutic targets. In ALS, the laboratory is assessing the pathogenic role of neuroinflammation, oxidative stress and the epigenome. Together with colleagues from the NCRI, the Sadri-Vakili lab uses biofluids to identify new diagnostic and prognostic biomarkers of disease. In addition, Dr. Sadri-Vakili works closely with partners in industry and routinely tests the therapeutic effects of novel small molecules and FDA-approved compounds in animal models of ALS.