Comparative transcriptomics reveal molecular convergence and divergence in parkinsonian disorders

Area of Science:

• Neuroscience
• Genomics
• Pathology

Background:

• Neurodegenerative parkinsonisms are diverse, incurable disorders with unknown pathogenesis.
• Previous transcriptomic studies were limited by small sample sizes and reproducibility issues.

Purpose of the Study:

• To conduct a large-scale comparative transcriptomic analysis of parkinsonian syndromes.
• To identify convergent and divergent gene expression and pathway profiles across different parkinsonisms and Alzheimer's disease.
• To provide an open-access resource for researchers studying these neurodegenerative diseases.

Main Methods:

• Comparative bulk transcriptomic analysis of 977 post-mortem prefrontal cortex samples.
• Included pathologically-confirmed Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, Alzheimer's disease, and controls.
• Accounted for covariates like age, sex, RNA integrity, brain bank origin, and cell type composition.

Main Results:

• All diseases showed neuronal transcript loss and glial signature enrichment, indicating neurodegeneration.
• Consistent downregulation of protein homeostasis, mitochondrial energy metabolism, RNA processing, and DNA repair pathways across parkinsonisms.
• Distinct molecular clustering observed for Lewy body diseases (Parkinson's disease, dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy, corticobasal degeneration), with multiple system atrophy in an intermediate position.

Conclusions:

• This study provides the most comprehensive comparative transcriptomic map of neurodegenerative parkinsonisms to date.
• Identified shared and distinct molecular mechanisms in α-synucleinopathies and tauopathies.
• The developed open-access web resource facilitates hypothesis generation and therapeutic target discovery for parkinsonian syndromes.