Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology

Thomas M. Goralski, Lindsay Meyerdirk, Libby Breton, Laura Brasseur, Kevin Kurgat, Daniella DeWeerd, Lisa Turner, Katelyn Becker, Marie Adams, Daniel J. Newhouse and Michael X. Henderson ()
Additional contact information
Thomas M. Goralski: Van Andel Institute
Lindsay Meyerdirk: Van Andel Institute
Libby Breton: Van Andel Institute
Laura Brasseur: Van Andel Institute
Kevin Kurgat: Van Andel Institute
Daniella DeWeerd: Van Andel Institute
Lisa Turner: Van Andel Institute Pathology Core
Katelyn Becker: Van Andel Institute Genomics Core
Marie Adams: Van Andel Institute Genomics Core
Daniel J. Newhouse: NanoString Technologies
Michael X. Henderson: Van Andel Institute

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract A key hallmark of Parkinson’s disease (PD) is Lewy pathology. Composed of α-synuclein, Lewy pathology is found both in dopaminergic neurons that modulate motor function, and cortical regions that control cognitive function. Recent work has established the molecular identity of dopaminergic neurons susceptible to death, but little is known about cortical neurons susceptible to Lewy pathology or molecular changes induced by aggregates. In the current study, we use spatial transcriptomics to capture whole transcriptome signatures from cortical neurons with α-synuclein pathology compared to neurons without pathology. We find, both in PD and related PD dementia, dementia with Lewy bodies and in the pre-formed fibril α-synucleinopathy mouse model, that specific classes of excitatory neurons are vulnerable to developing Lewy pathology. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. Neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and describe a conserved signature of molecular dysfunction in both mice and humans.

Date: 2024
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DOI: 10.1038/s41467-024-47027-8

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