Down-regulation of ghrelin receptors on dopaminergic neurons in the substantia nigra contributes to Parkinson's disease-like motor dysfunction

Autor: Wado Akamatsu, Takefumi Sone, Hideyuki Okano, Chizuru Iwasawa, Naoko Kuzumaki, Miri Matsuo, Masahiro Shibasaki, Michiko Narita, Minoru Narita, Nobutaka Hattori, Kenichi Tanaka, Yusuke Hamada, Aya Maekawa, Yukari Suda
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
medicine.medical_specialty
Parkinson's disease
Ubiquitin-Protein Ligases
Induced Pluripotent Stem Cells
Down-Regulation
Substantia nigra
Biology
Motor Activity
lcsh:RC346-429
Cell Line
03 medical and health sciences
Cellular and Molecular Neuroscience
Gene Knockout Techniques
0302 clinical medicine
Internal medicine
Extrapyramidal disorder
medicine
Animals
Humans
Gene Knock-In Techniques
Receptor
Receptors
Ghrelin
Molecular Biology
lcsh:Neurology. Diseases of the nervous system
Dopamine neuron
Injections
Intraventricular
Pars compacta
Dopaminergic Neurons
Research
Dopaminergic
iPS
Cell Differentiation
Parkinson Disease
medicine.disease
Ghrelin
Motor coordination
Mice
Inbred C57BL
Substantia Nigra
030104 developmental biology
Endocrinology
Parkinson’s disease
GHSR
Oligopeptides
030217 neurology & neurosurgery
Zdroj: Molecular Brain
Molecular Brain, Vol 11, Iss 1, Pp 1-9 (2018)
ISSN: 1756-6606
Popis: 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. Electronic supplementary material The online version of this article (10.1186/s13041-018-0349-8) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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