Determinants of Basal Forebrain Cholinergic Neuron Vulnerability in Parkinson's Disease and LewyBody Dementia

Parkinsons disease (PD) poses one of the greatest healthcare challenges of our time. With the aging of the general population, theincidence of PD is expected to rise in coming decades. This wave will create not only a humanitarian crisis, but an unsustainable tax onsocietal resources. Although there are effective symptomatic therapies for the motor symptoms of PD (at least in the early stages of thedisease), there are not effective therapies for the non-motor, PD and the commonly co-morbid, Lewy body dementia (LBD). This unmetmedical need is identified as one of the FY19 PRP Focus Areas - Mechanisms of non-motor symptoms of PD from basic biology to clinicalapplication. This gap in clinical care reflects our poor grasp of disease mechanisms. While it is widely accepted that mitochondrialdysfunction, synucleinopathy and inflammation contribute to PD and LBD, it is far from clear why these disease mechanisms manifestthemselves in some neuronal populations and not others. All neurons rely upon proper protein handling. All neurons depend uponmitochondrial function. All neurons appear to be susceptible to the production of inflammatory cytokines and reactive oxygen species bynon-neuronal cells. Understanding the basis for this selective vulnerability could provide the insight needed to develop new, potenttherapies for nonmotor symptoms in PD. One of the most vulnerable types of neuron in PD, LBD and Alzheimers disease (AD) is the basalfor brain cholinergic neuron (BFCN). Release of acetylcholine (ACh) by BFCNs modulates the activity of large cortical networks, and thedegeneration of these neurons is widely thought to be a primary driver of the cognitive deficits accompanying PD, LBD and AD. Yet, verylittle is known about how or why these neurons should be vulnerable to mitochondrial dysfunction, synucleinopathy or inflammation.