Lewy Body Pathology in Neurodegenerative Diseases

Lewy body pathology is defined by intraneuronal inclusions composed primarily of aggregated α-synuclein. These inclusions are the hallmark of synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies, and they also feature in multiple system atrophy. The formation of Lewy bodies correlates with dopaminergic neuron loss in the substantia nigra, manifesting clinically as motor dysfunction, cognitive impairment and autonomic failure. Pathogenic α-synuclein adopts a β-sheet-rich conformation, propagates along neuroanatomical pathways in a prion-like manner and recruits endogenous protein to form inclusions. Early, prodromal stages can be identified by non-motor symptoms and incidental Lewy body disease, revealing molecular and cellular alterations that precede overt neuronal death. Understanding the biogenesis, structural organisation and regional vulnerability of Lewy bodies is key to developing disease-modifying therapies and diagnostic biomarkers.

Research from Nature Portfolio

Advanced spectroscopic analysis has elucidated the fine structure of Lewy bodies in human brain tissue. Using synchrotron Fourier transform infrared micro-spectroscopy, investigators mapped the distribution of secondary structure elements within authentic inclusions. These studies revealed a pronounced β-sheet signature, with higher β-sheet content in the halo region than in the core, which is enriched in proteins and lipids. This work provides a structural framework to compare in vitro amyloid models with patient-derived Lewy bodies, thereby informing efforts to screen aggregation inhibitors and design targeted imaging agents.

Lewy Body Pathology in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in lewy body pathology in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Lewy body: Intracellular inclusion composed mainly of aggregated α-synuclein and associated proteins.

α-Synuclein: A presynaptic protein prone to misfolding and aggregation in synucleinopathies.

Prodromal Parkinson’s disease: Early phase marked by non-motor symptoms and incidental Lewy body pathology before clinical diagnosis.

β-Sheet: Protein secondary structure characterised by hydrogen-bonded, sheet-like strands; a feature of amyloid aggregates.

Fourier transform infrared micro-spectroscopy (FTIR micro-spectroscopy): A technique using infrared light to probe molecular bond vibrations, revealing secondary structure in biological specimens.

References

1. Neuropathology of incidental Lewy body & prodromal Parkinson’s disease. Molecular Neurodegeneration (2023).
2. A topographical atlas of α-synuclein dosage and cell type-specific expression in adult mouse brain and peripheral organs. npj Parkinson's Disease (2024).
3. The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America (2020).
4. Initiation and propagation of α-synuclein aggregation in the nervous system. Molecular Neurodegeneration (2020).
5. Synchrotron FTIR micro-spectroscopy for structural analysis of Lewy bodies in the brain of Parkinson’s disease patients. Scientific Reports (2015).