Sulfamerazine as a Potential Modulator against α-Synuclein Aggregation and Associated Toxicity
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. The presence of Lewy bodies, primarily consisting of amyloid aggregates of the protein α-synuclein (α-Syn), is a common feature seen in dopaminergic neurons in (PD) patients. In the present study, we screened 2320 FDA-approved drugs and found 3 lead molecules, sulfamerazine, lathosterol, and tamoxifen, that reproducibly inhibited α-Syn fibrillation. Dose-response studies showed that sulfamerazine and lathosterol are relatively more potent than tamoxifen in inhibiting α-Syn aggregation. Among the lead compounds, sulfamerazine showed a significant reduction in α-Syn aggregation and associated toxicity in <i>Caenorhabditis elegans</i> model of PD. Sulfamerazine also reduced the accumulation of α-Syn aggregates in neuronal SH-SY5Y cells. Microscale thermophoresis confirmed the binding of sulfamerazine to α-Syn. NMR studies corroborated the binding of sulfamerazine with α-Syn and show that upon interaction, α-Syn is sequestered into large soluble dispersed assemblies, which is similar to as seen in transmission electron microscopy. We conclude that sulfamerazine and its derivatives hold promise as therapeutic agents against Parkinson's disease.
Authors
- Abhishek Sharma (ORCID: https://orcid.org/0000-0002-3077-482X)
- Malay Kanti Dey (ORCID: https://orcid.org/0000-0002-2926-2536)
- Krishna Upadhayay (ORCID: https://orcid.org/0000-0001-5973-1770)
- Arpit Tyagi (ORCID: https://orcid.org/0009-0006-7331-6219)
- Arpit Mehrotra (ORCID: https://orcid.org/0000-0002-0378-0247)
- Ashutosh Kumar (ORCID: https://orcid.org/0000-0002-5061-8162)
- Alka Rao (ORCID: https://orcid.org/0000-0002-5032-2169)
- Janni Nielsen
- Daniel E. Otzen (ORCID: https://orcid.org/0000-0002-2918-8989)
- Giulia Kleijwegt
- Rajlaxmi Panigrahi (ORCID: https://orcid.org/0000-0002-6848-5695)
- Mohd Aquib
- Nagesh Y. Kadam (ORCID: https://orcid.org/0000-0001-5236-1615)
- Priyanka Singh
- Deepak Sharma (ORCID: https://orcid.org/0000-0003-1104-575X)
- Prashant Singh (ORCID: https://orcid.org/0009-0002-8893-2373)
Institutions
- Indian Institute of Technology Bombay (IN)
- Aarhus University (DK)
- Bioscience (China) (CN)
- Bioengineering Center (RU)
- Institute of Microbial Technology (IN)
- Council of Scientific and Industrial Research (IN)
- Academy of Scientific and Innovative Research (IN)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2025-02-12
- DOI
- https://doi.org/10.1021/acschemneuro.4c00803
- Citations
- 3
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.17
Funders
- Indian Council of Medical Research
- Council of Scientific and Industrial Research, India
- Lundbeckfonden