Parkinson's Disease: From Metabolism to Genetics-A Comprehensive Review

Area of Science:

• Neuroscience
• Metabolic pathways
• Neurodegenerative disease research

Background:

• Parkinson's disease (PD) is characterized by progressive neurodegeneration, specifically dopaminergic neuron loss.
• Pathophysiology involves metabolic, inflammatory, and proteostatic disturbances.
• Current therapies offer symptomatic relief but don't fully address underlying disease mechanisms.

Purpose of the Study:

• To synthesize evidence on PD pathophysiology, focusing on interconnected metabolic axes.
• To analyze the interaction between current therapies and these axes.
• To explore the role of transcriptomic studies in identifying therapeutic targets and biomarkers for PD.

Main Methods:

• Narrative review of clinical, epidemiological, and experimental data.
• Analysis of RNA sequencing (RNA-Seq) and transcriptomic studies in human tissues.
• Integration of systems-level evidence to view PD pathophysiology.

Main Results:

• PD pathophysiology organized around three axes: metabolic dysfunction (mitochondria, glucose, lipids), oxidative stress, and neuroinflammation.
• Alpha-synuclein identified as a central integrator of these pathways.
• RNA-Seq reveals convergent gene expression changes in key cellular pathways.

Conclusions:

• Alpha-synuclein-centered metabolic failure and glial dysregulation are key therapeutic targets in Parkinson's disease.
• High-quality RNA-Seq and bioinformatics can define PD endotypes.
• These approaches may accelerate the development of disease-modifying interventions for PD.