Team Kaplitt

Study Rationale: A hallmark of Parkinson’s disease (PD) is the development of abnormal deposits throughout the brain composed of the alpha-synuclein protein. This pathology can be found in the gut too. Increasing evidence indicates that, in some patients, alpha-synuclein pathology may begin in the gut and spread to the brain through a nerve called the vagus, which directly connects the gut to the brain. An animal model developed by Team Kaplitt’s members reproduces many of these features seen in humans to allow study of these pathways and consequences of this advancing disease as it spreads throughout the brain.

Hypothesis: Team Kaplitt hypothesizes that specific vagus nerve cells are responsible for disease spread from gut to brain, with both vagus nerve activity and other factors such as gender and menopause affecting this spread, resulting in early symptoms such as sleep disorders seen in humans before development of movement problems.

Study Design: The first two goals will use genetic manipulation to study (a) what cells may be responsible for gut-to-brain spread of abnormal alpha-synuclein, (b) how disease spread affects normal vagus functions, and (c) how different levels of vagus activity influence disease spread. Team Kaplitt will also study the consequences of this type of gut-brain spread on development of early symptoms that may occur before the movement problems, particularly sleep disorders. Given the reduced risk of PD in women prior to menopause, Team Kaplitt’s final goal is to study these same problems in a novel animal model that mimics human menopause.

Impact on Diagnosis: The gene therapy methods used to block gut-brain spread in Team Kaplitt’s studies could be applied non-invasively to patients with diagnosed presence of gut alpha-synuclein pathology to prevent disease spread. Team Kaplitt’s sleep and menopause studies will further identify opportunities for early intervention and possible hormonal approaches to limiting effects of disease spread.