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 cellular autophagy and induced the 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)+ 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.