Anandi Chowdhury | Ph.D. Candidate
Indian Institute of Technology Delhi

Festival of Biologics Day 3 @ 12:00

Development of Novel Peptides to Significantly Prevent Alpha-Synuclein Fibril-Induced Neurodegeneration

• Pathogenic Mechanism of α-Synuclein Fibrils: α-Synuclein fibrils induce cytotoxicity in the brain leading to progressive neuronal loss, a hallmark of Parkinson’s disease, for which we designed an in-vitro drug screening model.
• Innovative Peptide-Based Inhibition: Using structural bioinformatics, we designed novel peptides that block α-synuclein fibril entry into neural cells, designed high-throughput binding and cytotoxicity studies that successfully prevents internalization of fibrils and halts neurodegeneration.
• Therapeutic Potential: Our findings demonstrate that these peptides mitigate the spread of toxic α-synuclein species, enhancing neural cell survival and offering a promising therapeutic avenue for Parkinson’s disease and related synucleinopathies.

Fibrils of α-synuclein, an intrinsically disordered protein (IDP), are major pathogenic agents in several neurodegenerative diseases, including Parkinson’s disease. The propagation of these α-synuclein fibrils between neuronal and glial cells exhibits prion-like behaviour, rendering them highly cytotoxic as they induce progressive neuronal loss, a hallmark of Parkinson’s disease. These fibrils form through the aggregation of α-synuclein oligomers into insoluble higher-order fibrillar structures, stabilizing fibril growth and conferring toxicity. We employed a structural bioinformatics approach to determine fragment complexes with a stable β-sheet geometry and to generate dimer structural ensembles using its energy landscape. Using this method, we designed various novel peptides that effectively reduce α-synuclein aggregation synucleinopathies. The binding of these peptides block the entry of α-synuclein fibrils into neural cells, thereby preventing their cytotoxic effects and mitigating the spread of neurodegenerative pathology. Our detailed bioanalytical investigation demonstrated that these designed peptide inhibitors significantly reduce the cellular internalization of toxic α-synuclein species, thereby limiting the spread of fibrils in the neural microenvironment. In an in-vitro model of the disease, we introduced these peptides and observed a significant reduction in prion-like cellular uptake and processing of α-synuclein preformed fibrils, resulting in enhanced survival of neural cells.  This advancement not only provides a novel therapeutic approach for Parkinson’s disease but also sets a precedent for targeting protein aggregation in other neurodegenerative conditions.

Anandi Chowdhury, Ph.D. Candidate, Indian Institute of Technology Delhi

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Anandi Chowdhury / Development of Novel Peptides to Significantly Prevent Alpha-Synuclein Fibril-Induced Neurodegeneration

Anandi Chowdhury, Ph.D. Candidate,
Indian Institute of Technology Delhi

Anandi Chowdhury is a researcher at the Centre of Excellence for Biopharmaceutical Technology, Indian Institute of Technology Delhi, India. With over seven years of experience in biopharmaceutical research, she specializes in protein aggregation, biologic stability, and the development of...

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