Investigator:
Vikram Khurana, MD, PhD
Name of Institution:
Brigham & Women’s Hospital / Harvard Medical School, Boston, MA
Project Title:
Molecular mechanisms of perturbed mRNA metabolism in alpha-synucleinopathy
Investigator Bio:
Vik Khurana M.D. Ph.D. is the inaugural incumbent of the Tracy T. Batchelor Endowed Chair in Neurology at Mass General Brigham, Chief of the Movement Disorders Division at Brigham and Women’s Hospital and Associate Professor of Neurology at Harvard Medical School. He holds faculty appointments at the Ann Romney Center of Neurologic Diseases, Harvard Stem Cell Institute and the Broad Institute of MIT and Harvard. Dr Khurana obtained his medical degree from the University of Sydney, Ph.D. in neurobiology from Harvard University, neurology training at Mass General Brigham and postdoctoral training at the Whitehead Institute.
At Mass General Brigham, Dr Khurana leads i) the Harvard Biomarkers Study (HBS 2.0), one of the most extensive longitudinal biomarker and natural history studies of neurodegenerative disease patients worldwide; ii) the precision medicine (MyTrial) program; iii) the American Parkinson’s Disease Association (APDA) Center for Advanced Research; iv) the Multiple System Atrophy (MSA) Center of Excellence. He is a current member of the scientific advisory board of APDA, the New York Stem Cell Foundation (NYSCF) and Mission MSA. He has co-founded two biotech companies focused on developing neurodegenerative disease therapies.
The Khurana Lab has pioneered “systems cell biology” – the combination of stem-cell biology, genomics and high-throughput cellular analyses – to understand the diverse presentations and outcomes of neurodegenerative diseases (“patient heterogeneity”), and to ultimately develop precision medicines. The lab focuses on “synucleinopathies”: degenerative movement disorders related to aggregation of the alpha-synuclein (aSyn) protein in the brain (Parkinson’s disease (PD), Lewy body dementia, MSA). The lab has identified i) aSyn signature pathologies in patient stem cells (Science 2013); ii) connections between genetic and environmental risk factors and aSyn aggregation (Cell Systems/Cell 2017, Nature Comm 2023); iii) new classes of small-molecule and genetic medicines (Nedd4 activators: Science 2013; SCD inhibitors: Cell Reports 2018; ATN1 ASOs); iv) a role for aSyn in regulating gene expression (Cell 2022); iv) methods that enable rapid development of aSyn pathologies in patient stem cells (Neuron 2024). These approaches are now being applied to other neurodegenerative disorders.
Khurana is a past Fulbright Scholar, NYSCF Robertson Stem Cell Investigator, ANA Derek Denny-Brown Neurological Scholar, Aligning Science Across Parkinson’s (ASAP) investigator and APDA George C. Cotzias Fellow.
Objective:
In this project we investigate whether α -synuclein exerts toxic effects on the cell by interacting with messenger RNA (mRNA)-binding proteins.
Background:
Mutations in α-synuclein can cause PD, definitively tying this protein to development of disease. Whether and how α-synuclein exerts a toxic effect on the cell, however, remains poorly understood. In order to understand what α-synuclein does in a PD neuron, we generate induced pluripotent stem cells (iPSC) from our PD patients with α-synuclein mutations, which can be differentiated into neuron and glia cells. Using these cells, we have explored genetic and physical interactions of α-synuclein, and discovered unexpectedly, that α-synuclein influences the biology of mRNA, the intermediary molecule between DNA and the proteins that it encodes. It does so by directly interacting with proteins that bind mRNA.
Methods/Design:
In our proposal, we will use IPSCs created from people with dementia and parkinsonism due to specific mutations in or over-expression of α-synuclein. Using these cells, we will investigate the changes to mRNA biology that can be attributed to changes in α-synuclein. In this proposal we thoroughly investigate the possibility that changes in the biology of mRNAs and the proteins that bind them is a key cellular pathology in synuclein related diseases.
Relevance to Diagnosis/Treatment of Parkinson’s disease:
If α-synuclein is shown to change mRNA functioning, this could lead to the identification of new therapeutic targets and potential gene therapy approaches.