Towards a comprehensive understanding of the neurotoxic spread of α-synuclein from gut to brain in Parkinson's disease

Parkinson’s disease (PD) is an age-related neurodegenerative disorder for which disease-modifying therapies do not currently exist and the underlying mechanisms remain incompletely understood. PD is characterized by the loss of dopaminergic and other neuronal cell types, and the formation of pathological Lewy body inclusions

containing aggregated α-synuclein protein. Increasing evidence suggests that α-synuclein aggregation may originate in neurons innervating the gastrointestinal tract, and spread to the central nervous system in a prion- like manner. While rodent models have demonstrated that gut-to-brain spreading of α-synuclein can occur and

results in neurodegeneration and behavioral decline, major challenges associated with the low-throughput nature of these model systems have hindered progress in the field. To address these issues and significantly accelerate the rate of discovery of novel disease mechanisms, we propose to generate new gut-to-brain α-synuclein

transmission models in C. elegans, a rapidly aging and highly genetically tractable model organism amenable to large-scale investigations. We will construct and integrate brain-wide maps of spreading α-synuclein pathology and neurodegeneration, revealing vulnerable and resilient neuronal cell types in the face of α-synuclein insult

from the gut. To decipher cell type-specific mechanisms that underlie these differential susceptibilities, we will use a combination of high-throughput screening and single cell RNA-sequencing. Known and predicted cell surface proteins will be systematically tested for a potential role as novel α-synuclein receptors, facilitating the

toxic invasion of α-synuclein into neurons. Nervous system-wide, single cell transcriptional analyses will provide powerful insights into both protective and detrimental factors responsible for the fate of neurons in the path of gut-to-brain α-synuclein transmission. Collectively, this work will constitute the most comprehensive investigation

to date of the mechanisms regulating α-synuclein neurotoxic propagation from the gut, linking cellular- and molecular-level events at unprecedented resolution, with neuronal degeneration and whole-organism behavioral dysfunction. Given the accessibility of the human gut to pharmacological and dietary interventions, the results of

this study may inform early therapeutic strategies that hold great promise to halt or even prevent PD progression.