Spatial transcriptomics reveals molecular dysfunction associated with Lewy pathology.

Area of Science:

• Neuroscience
• Pathology
• Genomics

Background:

• Lewy pathology, primarily α-synuclein aggregates, defines Parkinson's disease (PD).
• While dopaminergic neuron death is studied, the specific neuronal vulnerability and molecular consequences of Lewy pathology in the cortex remain unclear.
• Understanding these aspects is crucial for elucidating PD pathogenesis and cognitive decline.

Approach:

• Spatial transcriptomics was employed to analyze whole transcriptome signatures of cortical neurons with and without Lewy pathology.
• This approach allowed for the direct comparison of gene expression within the same brain samples, in both human PD cases and a mouse model.
• The study focused on identifying specific neuronal subtypes vulnerable to Lewy pathology and characterizing the molecular alterations within these neurons.

Key Points:

• Specific classes of excitatory neurons in the cortex are identified as vulnerable to developing Lewy pathology in both human PD and a PD mouse model.
• A conserved gene expression signature, termed the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature, was identified in neurons bearing Lewy aggregates.
• The LAMDA signature reveals downregulation of synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes, alongside upregulation of DNA repair and complement/cytokine genes.

Conclusions:

• Neurons with Lewy pathology exhibit significant molecular dysfunction, including impaired cellular maintenance pathways.
• Upregulation of DNA repair genes is accompanied by the activation of apoptotic pathways, suggesting a programmed cell death response when repair mechanisms fail.
• These findings pinpoint vulnerable neuronal populations in the PD cortex and provide a conserved molecular signature of dysfunction, offering insights into PD progression and potential therapeutic targets.