Gut-Initiated Alpha Synuclein Fibrils Drive Parkinson's Disease Phenotypes: Temporal Mapping of non-Motor Symptoms and REM Sleep Behavior Disorder.

Parkinson's disease (PD) is characterized by progressive motor as well as less recognized non-motor symptoms that arise often years before motor manifestation, including sleep and gastrointestinal disturbances. Despite the heavy burden on the patient's quality of life, these non-motor manifestations are poorly understood. To elucidate the temporal dynamics of the disease, we employed a mouse model involving injection of alpha-synuclein (αSyn) pre-formed fibrils (PFF) in the duodenum and antrum as a gut-brain model of Parkinsonism. Using anatomical mapping of αSyn-PFF propagation and behavioral and physiological characterizations, we unveil a correlation between post-injection time the temporal dynamics of αSyn propagation and non-motor/motor manifestations of the disease. We highlight the concurrent presence of αSyn aggregates in key brain regions, expressing acetylcholine or dopamine, involved in sleep duration, wakefulness, and particularly REM-associated atonia corresponding to REM behavioral disorder-like symptoms. This study presents a novel and in-depth exploration into the multifaceted nature of PD, unraveling the complex connections between α-synucleinopathies, gut-brain connectivity, and the emergence of non-motor phenotypes.