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Abstract
Ghrelin exerts a wide range of physiological actions throughout the body and appears to be a promising target for disease therapy. Endogenous ghrelin receptors (GHSRs) are present in extrahypothalamic sites including the substantia nigra pars compacta (SNc), which is related to phenotypic dysregulation or frank degeneration in Parkinson’s disease (PD). Here we found a dramatic decrease in the expression of GHSR in PD-specific induced pluripotent stem cell (iPSC)-derived dopaminergic (DAnergic) neurons generated from patients carrying parkin gene (PARK2) mutations compared to those from healthy controls. Consistently, a significant decrease in the expression of GHSR was found in DAnergic neurons of isogenic PARK2-iPSC lines that mimicked loss of function of the PARK2 gene through CRISPR Cas9 technology. Furthermore, either intracerebroventricular injection or microinjection into the SNc of the selective GHSR1a antagonist [D-Lys3]-GHRP6 in normal mice produced cataleptic behaviors related to dysfunction of motor coordination. These findings suggest that the down-regulation of GHSRs in SNc-DA neurons induced the initial dysfunction of DA neurons, leading to extrapyramidal disorder under PD.
Highlights
Parkinson’s disease (PD) is a common, debilitating, neurodegenerative disorder that is associated with progressive motor dysfunction
Most of the differentiated cells derived from control and PARK2-specific induced pluripotent stem cell (iPSC) were labeled by antibodies to βIII-tubulin and TH (Fig. 1b)
There was no significant difference in the ratio of TH-positive DA neurons between control and PARK2 iPSCs-derived neurons (Fig. 1c)
Summary
Parkinson’s disease (PD) is a common, debilitating, neurodegenerative disorder that is associated with progressive motor dysfunction. PD is characterized by the progressive loss of dopamine (DA) neurons, and the DA neurons that degenerate in PD primarily project to the substantia nigra pars compacta (SNc). The motor symptoms of PD manifest only after a significant loss of striatal (70–80%) DA concentration in the brain and are seen relatively late in disease progression. The exact mechanism by which PARK2 causes PD-like syndromes and why dopaminergic neurons are primarily affected by a ubiquitously expressed mutation remain unknown [4, 5]. A monogenic form of PD-specific iPSCs-derived DA neurons could provide important clues for elucidating the pathogenesis of PD
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