New insights underlying the early events of dopaminergic dysfunction in Parkinson's Disease

Alpha melanocyte-stimulating hormone (-MSH) is an autocrine factor released by activated microglia during neuroinflammation and is elevated in the cerebrospinal fluid of Parkinsons disease (PD) patients. -MSH impaired cellular autophagy and induced the accumulation of alpha-synuclein in a melanized human dopaminergic cell model. Increased -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 -MSH leads to impairment of autophagy resulting in abnormal accumulation of proteins, dopaminergic dysfunction and motor deficits. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/313957v3_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@78c4a2org.highwire.dtl.DTLVardef@b59f50org.highwire.dtl.DTLVardef@1ee74f2org.highwire.dtl.DTLVardef@3fbfef_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance statementWe now show that a naturally occurring compound increased in the brain of Parkinsons disease (PD) patients, called -MSH, can trigger abnormal accumulation of alpha-synuclein in a dopaminergic cell model. Increasing -MSH in the brain of mice resulted in motor symptoms and abnormal gait. Increasing dopamine activity in these mice using Levodopa or Pramipexole restored normal gait, 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 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. AbbreviationsPD, Parkinsons disease; DN, dopaminergic neuron; -MSH, alpha-melanocyte stimulating hormone; TH, tyrosine hydroxylase; SNpc, substantia nigra pars compacta; VTA, ventral tegmental area; CNS, central nervous system; CSF, cerebrospinal fluid; INS, intranasal; ASIP, agouti-signaling protein; MC1R, melanocortin receptor 1; ROS, reactive-oxygen species; MSA, multiple system atrophy