Neuroinflammation in Proteinopathies of the Central Nervous System

Neuroinflammation coincides with misfolded protein aggregation in diverse central nervous system disorders. In Alzheimer’s disease, Parkinson’s disease, Lewy body dementia and multiple system atrophy, pathologic conformers of amyloid-β, tau and α-synuclein accumulate within neurons and glia, triggering innate and adaptive immune responses. Activated microglia and astrocytes release cytokines, complement factors and reactive oxygen species in an attempt to contain or clear aggregates. However, persistent or dysregulated activation leads to secondary damage, synaptic loss and neuronal death. The resulting cycle of protein misfolding and inflammation contributes to disease progression, clinical heterogeneity and therapeutic resistance. Recent insights have highlighted blood–brain barrier dysfunction, peripheral immune cell infiltration and shifts from pro- to anti-inflammatory phenotypes over disease stages, revealing complex spatial and temporal dynamics. Understanding how individual protein species interact with glial receptors and inflammatory cascades is crucial to developing targeted interventions that restore immune homeostasis without impairing protective functions.

Research from Nature Portfolio

Recent system-level proteogenomic network analyses in Parkinson’s disease have elucidated the molecular interplay between genetic risk variants and dysregulated proteome pathways. Leveraging large-scale population proteomics, researchers identified hundreds of proteins enriched in cytokine receptor interactions, lysosomal function and immune signalling. A subset of mediators, including galectin-3 binding protein and lysosomal enzymes, emerged as potential indirect effectors of disease pathogenesis. These findings refine our understanding of genome–proteome crosstalk in synucleinopathies and provide a blueprint for pinpointing novel therapeutic targets within inflammatory networks.

Neuroinflammation in Proteinopathies of the Central Nervous System publication trend

The graph below shows the total number of articles in neuroinflammation in proteinopathies of the central nervous system across all publications each year (not limited to Nature Index journals).

Technical terms

Neuroinflammation: Inflammatory response within the central nervous system involving glia and immune molecules.

Proteinopathy: Disease characterised by misfolded protein aggregates in neural tissue.

Microglia: Innate immune cells of the brain that mediate inflammatory and phagocytic functions.

Astrocyte: Glial cell that supports neurons, regulates the blood–brain barrier and participates in immune signalling.

Cytokine: Small signalling protein that modulates immune and inflammatory responses.

α-synuclein: Neuronal protein prone to misfolding and aggregation in synucleinopathies.

Proteogenomics: Integrated analysis of proteomic and genomic data to map disease pathways.

Galectin-3: Carbohydrate-binding protein implicated in microglial activation and protein aggregate modulation.

References

1. Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease. Nature Communications (2024).
2. Galectin-3 shapes toxic alpha-synuclein strains in Parkinson’s disease. Acta Neuropathologica (2023).
3. Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review. International Journal of Molecular Sciences (2023).
4. T Lymphocytes and Their Potential Role in Dementia with Lewy Bodies. Cells (2023).