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Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology.
Thomas M Goralski1,2, Lindsay Meyerdirk1,2, Libby Breton1,2
1Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503, USA.
Nature Communications
|March 27, 2024
Summary
Researchers identified specific cortical neurons vulnerable to Lewy pathology in Parkinson's disease (PD). They discovered a conserved molecular dysfunction signature (LAMDA) in affected neurons, impacting synaptic and mitochondrial functions.
Area of Science:
- Neuroscience
- Molecular Biology
- Genomics
Background:
- Lewy pathology, primarily α-synuclein aggregates, is a hallmark of Parkinson's disease (PD) and related dementias.
- While dopaminergic neuron vulnerability in PD is known, cortical neuron susceptibility to Lewy pathology and its molecular consequences remain poorly understood.
Purpose of the Study:
- To identify specific cortical neuron subtypes vulnerable to α-synuclein pathology.
- To characterize the molecular changes within cortical neurons bearing Lewy pathology.
Main Methods:
- Spatial transcriptomics was employed to analyze whole transcriptome signatures in human and mouse cortical neurons with and without α-synuclein pathology.
- Comparative analysis was performed across human PD, dementia with Lewy bodies, and a mouse model of α-synucleinopathy.
Main Results:
- Specific classes of excitatory neurons were found to be vulnerable to Lewy pathology in both human patients and a mouse model.
- A conserved gene expression signature, termed Lewy-associated molecular dysfunction from aggregates (LAMDA), was identified in aggregate-bearing neurons.
- LAMDA signature involves downregulation of synaptic, mitochondrial, and cytoskeletal genes, and upregulation of DNA repair and immune-related genes.
Conclusions:
- This study pinpoints vulnerable cortical neuron populations in Parkinson's disease.
- A conserved molecular dysfunction signature (LAMDA) provides insights into the cellular mechanisms underlying Lewy pathology in the cortex.
- Findings contribute to understanding cognitive decline in PD and related synucleinopathies.
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