Alpha-synuclein aggregation induces prominent cellular lipid changes as revealed by Raman spectroscopy and machine learning analysis

Topic: Brain proteins, microglia and lab models

Abstract The aggregation of α-synuclein is a central neuropathological hallmark in neurodegenerative disorders known as Lewy body diseases, including Parkinson's disease and dementia with Lewy bodies. In the aggregation process, α-synuclein transitions from its native disordered/α-helical form to a β-sheet-rich structure, forming oligomers and protofibrils that accumulate into Lewy bodies, in a process that is thought to underlie neurodegeneration. Lipids are thought to play a critical role in this process by facilitating α-synuclein aggregation and contributing to cell toxicity, possibly through ceramide production. This study aimed to investigate biochemical changes associated with α-synuclein aggregation, focusing on lipid changes, using Raman spectroscopy coupled with machine learning. HEK293, Neuro2a and SH-SY5Y expressing increased levels of α-synuclein were treated with sonicated α-synuclein pre-formed fibrils, to model seeded aggregation. Raman spectroscopy, complemented by an in-house lipid spectral library, was used to monitor the aggregation process and its effects on cellular viability over 14 days. We detected α-synuclein aggregation by assessing β-sheet peaks at 1045 cm⁻1, in cells treated with α-synuclein pre-formed fibrils, using machine learning (principal component analysis and uniform manifold approximation and projection) analysis based on Raman spectral features. Changes in lipid profiles, and especially sphingolipids, including a decrease in sphingomyelin and increase in ceramides, were observed, consistent with oxidative stress and apoptosis. Altogether, our study informs on biochemical alterations that can be considered for the design of therapeutic strategies for Parkinson's disease and related synucleinopathies.

Key findings

• This study aimed to investigate biochemical changes associated with α-synuclein aggregation, focusing on lipid changes, using Raman spectroscopy coupled with machine learning.

Why it matters

This laboratory study used Raman spectroscopy and machine learning to examine lipid changes during alpha-synuclein aggregation in cells, which is relevant to Lewy body diseases. It is early cell-based work and does not test any treatment, cure or prevention in people.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1093/braincomms/fcaf133
• PubMed: 40226383
• Original source →
• Free full text: Brain Communications →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{coles2025-40226383,
  author  = {Coles, Nathan P. and Elsheikh, Suzan and Quesnel, Agathe and Butler, Lucy and Achadu, Ojodomo J. and Islam, Meez and Kalesh, Karunakaran and Occhipinti, Annalisa and others},
  title   = {{Alpha-synuclein aggregation induces prominent cellular lipid changes as revealed by Raman spectroscopy and machine learning analysis}},
  journal = {Brain Communications},
  year    = {2025},
  doi     = {10.1093/braincomms/fcaf133},
  pmid    = {40226383},
  url     = {https://doi.org/10.1093/braincomms/fcaf133}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies Proceedings of the National Academy of Sciences of the United States of America · 1998-05-01 · usefulness score 58/100 · Lewy body dementia
• Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death Neuron · 2011-10-01 · usefulness score 56/100 · Lewy body dementia
• Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop Neurology · 1996-11-01 · usefulness score 55/100 · Getting a diagnosis
• Addition of exogenous α-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous α-synuclein to Lewy body and Lewy neurite-like aggregates Nature protocols · 2014-08-14 · usefulness score 54/100 · Lewy body dementia
• Chaperone-mediated autophagy markers in Parkinson disease brains Archives of neurology · 2010-08-09 · usefulness score 47/100 · Lewy body dementia
• Molecular Insights into α-Synuclein Fibrillation: A Raman Spectroscopy and Machine Learning Approach ACS Chemical Neuroscience · 2025-01-28 · usefulness score 40/100 · Digital health tools

Later studies that cite this one

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• A modified α-synuclein seed amplification assay in Lewy body dementia using Raman spectroscopy and machine learning analysis Journal of Neuroscience Methods · 2025-11-15 · usefulness score 36/100 · Digital health tools

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