Pathological Mechanisms in Neurodegenerative Disorders

Neurodegenerative disorders arise from progressive loss of neuronal structure and function, driven largely by the misfolding, aggregation and impaired clearance of key proteins. Central to this process are proteinopathies involving tau, α-synuclein and amyloid-β, which form neurofibrillary tangles, Lewy bodies and extracellular plaques, respectively. These aberrant assemblies trigger synaptic dysfunction, axonal transport deficits, cellular stress and ultimately cell death. A failure of proteostasis networks—encompassing molecular chaperones, the ubiquitin-proteasome system and autophagy—allows toxic species to accumulate. Cross-seeding interactions between different misfolded proteins and prion-like propagation of aggregates across neural circuits further amplify pathology. Mitochondrial impairment, oxidative stress and chronic neuroinflammation contribute additional layers of neuronal vulnerability. Together, these interconnected mechanisms underpin the clinical heterogeneity and overlap seen across Alzheimer’s disease, Parkinson’s disease, Lewy body dementia and related tauopathies and synucleinopathies. Understanding how these pathways converge to drive neurodegeneration offers routes to global therapeutic interventions and early biomarker development.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Pathological Mechanisms in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in pathological mechanisms in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Proteostasis: The cellular network that maintains protein folding, trafficking and degradation to prevent toxic accumulation.

Proteinopathy: A disease process characterised by abnormal aggregation of specific proteins in the nervous system.

Tauopathy: A class of disorders marked by pathological aggregation of tau protein into neurofibrillary tangles.

Synucleinopathy: A group of diseases in which α-synuclein misfolds and accumulates as Lewy bodies or related inclusions.

Cross-seeding: The process by which aggregates of one misfolded protein promote the misfolding and aggregation of another.

Prion-like propagation: The spread of protein aggregates from cell to cell, propagating misfolded conformations through neural networks.

References

1. Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration. Translational Neurodegeneration (2024).
2. α‑Synuclein Aggregation Is Triggered by Oligomeric Amyloid‑β 42 via Heterogeneous Primary Nucleation. Journal of the American Chemical Society (2023).
3. Distinct tau and alpha-synuclein molecular signatures in Alzheimer’s disease with and without Lewy bodies and Parkinson’s disease with dementia. Acta Neuropathologica (2024).