REGION-SPECIFIC VULNERABILITY OF THE LEWY BODY DEMENTIA’S BRAIN
PROJECT SUMMARY
Lewy Body Dementia (LBD) is a progressive neurodegenerative disorder characterized by aggregation of the a-
synuclein (a-syn) into intracellular inclusions called Lewy bodies (LB) and Lewy neurites (LN). This form of
dementia belongs to a class of neurodegenerative diseases termed “synucleinopathies.” LBD is the most
common neurodegenerative dementia after Alzheimer’s disease. In LBD, dementia usually proceeds to the onset
of parkinsonian motor symptoms with neurobehavioral symptoms that may be accompanied by both cognitive
and motoric dysfunction. While various misfolded oligomers, primarily constituted of a-syn, are associated with
the development of dementia along with neuronal loss, there is still insufficient understanding of the pathogenesis
process. Especially, particular brain areas such as the limbic system and neocortex are more vulnerable than
other regions. Researchers have considered that the answer to this question will provide a key clue to
understanding the pathogenesis mechanism. Inter-cellular crosstalk of neurons, microglia, and astrocytes results
in complex physiologies and cellular behaviors, potentially leading to neuronal loss. Moreover, there is brain
region-specific heterogeneity in cellular populations of neurons, microglia, and astrocytes that can contribute to
the region-specific vulnerability of the LBD brain. Therefore, information on cell-type-specific and single-cell-
specific proteome and transcriptome over multiple brain regions is indispensable for understanding this complex
mechanism. To study this complex mechanism, the selection of the right aminal model that best recapitulates
the human LBD pathogenesis process is crucial. The mouse model that recapitulates the Braak hypothesis would
serve as the best animal model and we recently have generated this mouse model (gut-brain a-syn model)
successfully by injecting a-syn to the gut. To study the regional vulnerability of LBD using the mouse model, we
propose 1) to study region- and cell-type-specific proteome of the brain of the gut-brain a-syn model using
BONCAT and xMD, 2) to study region- and single-cell-specific transcriptome of the brain of the gut-brain a-syn
model using HiF-snRNAseq, 3) to perform integrative bioinformatic analysis and validate the affected pathways
found in the mouse models using the human brain. Cell-type-specific proteome analysis and single-cell
transcriptome analyses over multiple brain regions of the gut-brain a-syn model proposed in this application will
enable us to identify region- and cell-type-specific signaling pathways that are involved in region-specific
vulnerabilities to pathological a-syn. This novel information will contribute to a better understanding of LBD
pathogenesis. Furthermore, these approaches can be expanded to studying pathogenesis mechanisms of other
neurodegenerative diseases.