Abstract
We now show that key processes implicated in synuclein pathogenesis such as impairment of cellular autophagy and alpha-synuclein (α-syn) aggregation are induced by alpha-melanocyte stimulating hormone (alpha-MSH), a microglia-secreted anti-inflammatory mediator. We employed the pigmented melanoma cell line MNT-1 as a novel in-vitro cell model of melanin-containing dopaminergic neurons (DNs) of the substantia nigra (SN). Melanin levels serve as a reliable readout of autophagy in MNT-1 and exposure to alpha-MSH resulted in a decrease in melanin and a failure to slow down glucose consumption, which induced cell death by apoptosis. ASIP (agouti-signaling protein), the natural biologic inhibitor of alpha-MSH, blocked and reversed the effects of alpha-MSH. Mice administered intranasal alpha-MSH exhibited progressive decline in gait, a prevalent condition seen in patients with Parkinson’s Disease (PD). Moreover, we observed what may be α-syn aggregation in the SN pars compacta (SNpc). SNpc and striatal tyrosine hydroxylase (TH) density showed very modest reduction in this animal PD model consistent with PD pathology at the very early stage of disease.
Fundamental Questions Addressed by this Study
What may be the pathophysiologic link between neuroinflammation and impairment of autophagy in PD?
What may be a microglia-derived mediator that impairs autophagy and induces alpha-synuclein aggregation in dopaminergic neurons in PD?
What drives neurotoxicity that could lead to oxidative stress and ROS-mediated cell loss in PD?
Competing Interest Statement
The authors have declared no competing interest.
