Neurodegenerative Mechanisms and Therapeutic Strategies in Parkinson's Disease

Parkinson’s disease is characterised by progressive loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms such as bradykinesia, rigidity and tremor, as well as a range of non-motor features. Central to its pathogenesis are misfolded α-synuclein aggregates, mitochondrial dysfunction, oxidative stress, neuroinflammation, impaired proteostasis and ferroptosis. These interconnected mechanisms drive neuronal damage and synaptic failure. Current therapeutic strategies extend beyond symptomatic dopaminergic replacement to include immunotherapies targeting α-synuclein, small molecules that inhibit aggregation, antioxidants and iron chelators to counteract oxidative stress, agents that promote mitochondrial biogenesis or mitophagy, modulators of inflammatory pathways, and gene therapies for familial forms. Advances in fluid and imaging biomarkers now promise earlier diagnosis and patient stratification. By integrating these multifaceted approaches, researchers aim to achieve neuroprotection, slow disease progression and restore neuronal function.

Research from Nature Portfolio

Recent work has established a blood-based proteomic panel capable of identifying individuals at the pre-motor stage of Parkinson’s disease up to seven years before clinical onset. Using targeted mass spectrometry and machine-learning algorithms, eight proteins involved in endoplasmic reticulum stress, complement activation and extracellular matrix remodelling were quantified in cohorts of symptomatic patients, pre-motor individuals with REM sleep behaviour disorder and healthy controls. The model achieved high sensitivity and specificity, correlated with symptom severity and offers a minimally invasive diagnostic tool to enrich clinical trials for disease-modifying therapies.

Neurodegenerative Mechanisms and Therapeutic Strategies in Parkinson's Disease publication trend

The graph below shows the total number of articles in neurodegenerative mechanisms and therapeutic strategies in parkinson's disease across all publications each year (not limited to Nature Index journals).

Technical terms

α-synuclein: Neuronal protein prone to misfolding and aggregation, forming intracellular Lewy bodies.

Neuroinflammation: Activation of brain immune cells, notably microglia, contributing to neuronal injury.

Oxidative stress: Imbalance between reactive oxygen species production and antioxidant defences.

Mitochondrial biogenesis: Cellular process generating new mitochondria to maintain energy homeostasis.

Ferroptosis: Iron-dependent regulated cell death driven by lipid peroxidation.

Proteomics: Large-scale analysis of proteins, their structures and functions, often via mass spectrometry.

Biomarker: Measurable indicator of a biological state used for diagnosis or monitoring disease progression.

References

1. Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions. Signal Transduction and Targeted Therapy (2023).
2. Plasma proteomics identify biomarkers predicting Parkinson’s disease up to 7 years before symptom onset. Nature Communications (2024).
3. Ameliorating Mitochondrial Dysfunction of Neurons by Biomimetic Targeting Nanoparticles Mediated Mitochondrial Biogenesis to Boost the Therapy of Parkinson's Disease. Advanced Science (2023).