Abstract
Alpha melanocyte-stimulating hormone (α-MSH) is an autocrine factor released by activated microglia during neuroinflammation and is elevated in the cerebrospinal fluid of Parkinson’s disease (PD) patients. α-MSH impaired autophagy and accumulation of alpha-synuclein in a melanized human dopaminergic cell model. Increased α-MSH in the brain of mice resulted in the gradual worsening of abnormal gait. Dopamine replacement with L-dopa/Benserazide or treatment with a dopamine receptor agonist, Pramipexole, temporarily restored normal gait, suggesting dopamine deficiency as the cause of motor deficits in these mice. Notably, end-stage disease pathology such as neuronal cell loss, reduction in tyrosine hydroxylase (TH)-positive fiber density in the striatum and pSer129+ alpha-synuclein inclusions were absent. Rather, autophagic dysfunction was observed in the dopaminergic neuronal (DN) cell population within the substantia nigra pars compacta and ventral tegmental area. Moreover, increased expression of TH was observed in the striatum, suggesting a compensatory response to diminished dopamine levels. Our findings provide new insights into the early events that underlie neurodegeneration in PD and suggest that exposure of DNs to elevated levels of microglial α-MSH leads to impairment of autophagy resulting in abnormal accumulation of proteins, dopaminergic dysfunction and motor deficits.
Significance statement We now show that a naturally occurring compound found elevated in the brains of Parkinson’s disease (PD) patients, called α-MSH, can trigger abnormal accumulation of alpha-synuclein in a dopaminergic cell. Increasing α-MSH in the brains of mice resulted in motor symptoms seen in PD. Increasing dopamine activity in these mice using Levodopa or Pramipexole restored normal movements, suggesting that the mice were deficient in dopamine, as seen in PD. We now describe a cell and an animal model that can reproduce the early stages of dopaminergic cellular dysfunction in PD. These new pre-clinical research tools will be useful in developing effective drugs that will stop the progression of the disease in patients who suffer from PD.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
The figures have been reformatted for submission. We have expanded the animal studies and included additional histological assessments in support of our original thesis. Additional supplemental materials have been added.
