{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:49:20Z","timestamp":1788922160287,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T00:00:00Z","timestamp":1735516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["JP22K06814"],"award-info":[{"award-number":["JP22K06814"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent findings have revealed that melanocortin 1 receptor (MC1R) deficiency leads to Parkinson\u2019s disease-like dopaminergic neurodegeneration in the substantia nigra (SN). However, its precise distribution and expressing-cell type in the SN remain unclear. Therefore, in this study, we analyzed the localization and characteristics of MC1R in the SN using histological methods, including in situ hybridization and immunohistochemistry. Our findings reveal that MC1R was slightly present in dopaminergic neurons in the ventral tier of SN pars compacta dorsal (vSNCD), a region particularly vulnerable to PD-related neurodegeneration. Notably, we discovered that MC1R is highly present in parvalbumin (PV)-positive neurons, which were also vesicular GABA transporter messenger RNA-expressing inhibitory neurons of the lateral SN pars reticulata (lSNR). Intracellular analysis demonstrated that MC1R was present not only in the plasma membrane but also in mitochondrial and endoplasmic reticulum membranes. Furthermore, MC1R co-localized with attractin (Atrn), a known MC1R modulator, in nearly all MC1R-positive neurons. Therefore, it has been suggested that MC1R and Atrn work together to regulate dopaminergic neurons in the SN through both direct expression and indirect modulation via PV-positive inhibitory neurons. These findings provide new insights into MC1R\u2019s role in the SN and its potential contribution to PD pathophysiology<\/jats:p>","DOI":"10.3390\/ijms26010236","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T07:51:57Z","timestamp":1735631517000},"page":"236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Localization of Melanocortin 1 Receptor in the Substantia Nigra"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8083-7465","authenticated-orcid":false,"given":"Ayuka","family":"Ehara","sequence":"first","affiliation":[{"name":"Department of Anatomy, Dokkyo Medical University School of Medicine, 880 Kita-Kobayashi, Mibu-machi, Shimotsuga-gun 321-0293, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nozomi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Functional Morphology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose 204-8588, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6717-7167","authenticated-orcid":false,"given":"Kazuhiko","family":"Nakadate","sequence":"additional","affiliation":[{"name":"Department of Functional Morphology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose 204-8588, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuko","family":"Tokuda","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Dokkyo Medical University School of Medicine, 880 Kita-Kobayashi, Mibu-machi, Shimotsuga-gun 321-0293, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.1002\/ijc.23396","article-title":"MC1R variants, melanoma and red hair color phenotype: A meta-analysis","volume":"122","author":"Raimondi","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1159\/000097851","article-title":"Mortality due to amyotrophic lateral sclerosis and Parkinson\u2019s disease among melanoma patients","volume":"28","author":"Baade","year":"2007","journal-title":"Neuroepidemiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1001\/archneurol.2010.1","article-title":"Increased melanoma risk in Parkinson disease: A prospective clinicopathological study","volume":"67","author":"Bertoni","year":"2010","journal-title":"Arch. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/mds.25734","article-title":"Malignant melanoma in early-treated Parkinson\u2019s disease: The NET-PD trial","volume":"29","author":"Constantinescu","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1097\/00001756-199511000-00022","article-title":"Expression of melanocortin 1 receptor in periaqueductal gray matter","volume":"6","author":"Xia","year":"1995","journal-title":"Neuroreport"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1159\/000097313","article-title":"A potential mechanism of local anti-inflammatory action of alpha-melanocyte-stimulating hormone within the brain: Modulation of tumor necrosis factor-alpha production by human astrocytic cells","volume":"4","author":"Wong","year":"1997","journal-title":"Neuroimmunomodulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/ana.24852","article-title":"The melanoma-linked \u201credhead\u201d MC1R influences dopaminergic neuron survival","volume":"81","author":"Chen","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13024-022-00520-4","article-title":"Melanocortin 1 receptor activation protects against alpha-synuclein pathologies in models of Parkinson\u2019s disease","volume":"17","author":"Cai","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1007\/s11481-023-10094-7","article-title":"Peripheral MC1R Activation Modulates Immune Responses and is Neuroprotective in a Mouse Model of Parkinson\u2019s Disease","volume":"18","author":"Srivastava","year":"2023","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1002\/ar.24934","article-title":"Type 1 melanocortin receptors in pro-opiomelanocortin-, vasopressin-, and oxytocin-immunopositive neurons in different areas of mouse brain","volume":"306","author":"Romanova","year":"2023","journal-title":"Anat. Rec."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/83741","article-title":"A biochemical function for attractin in agouti-induced pigmentation and obesity","volume":"27","author":"He","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0014-5793(99)01494-5","article-title":"Distribution of Mahogany\/Attractin mRNA in the rat central nervous system","volume":"462","author":"Lu","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/S0306-4522(99)00451-0","article-title":"Age-related dopamine deficiency in the mesostriatal dopamine system of zitter mutant rats: Regional fiber vulnerability in the striatum and the olfactory tubercle","volume":"95","author":"Ueda","year":"2000","journal-title":"Neuroscience"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1007\/s00401-006-0058-8","article-title":"Progressive dopaminergic neurodegeneration of substantia nigra in the zitter mutant rat","volume":"112","author":"Nakadate","year":"2006","journal-title":"Acta Neuropathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1002\/cne.21662","article-title":"Attractin\/mahogany protein expression in the rodent central nervous system","volume":"508","author":"Nakadate","year":"2008","journal-title":"J. Comp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1267\/ahc.09018","article-title":"Application of Fluoro-Jade C in acute and chronic neurodegeneration models: Utilities and staining differences","volume":"42","author":"Ehara","year":"2009","journal-title":"Acta Histochem. Cytochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1093\/brain\/122.8.1437","article-title":"The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson\u2019s disease","volume":"122","author":"Damier","year":"1999","journal-title":"Brain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.nbd.2003.09.001","article-title":"ALDH1 mRNA: Presence in human dopamine neurons and decreases in substantia nigra in Parkinson\u2019s disease and in the ventral tegmental area in schizophrenia","volume":"14","author":"Galter","year":"2003","journal-title":"Neurobiol. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3032","DOI":"10.1172\/JCI72176","article-title":"Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation","volume":"124","author":"Liu","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.celrep.2014.10.008","article-title":"Defining midbrain dopaminergic neuron diversity by single-cell gene expression profiling","volume":"9","author":"Poulin","year":"2014","journal-title":"Cell Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41531-024-00777-0","article-title":"Calbindin and Girk2\/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson\u2019s disease model","volume":"10","author":"Carrillo","year":"2024","journal-title":"NPJ Parkinson Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/39908","article-title":"Identification and characterization of the vesicular GABA transporter","volume":"389","author":"McIntire","year":"1997","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9733","DOI":"10.1523\/JNEUROSCI.18-23-09733.1998","article-title":"The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons","volume":"18","author":"Chaudhry","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1002\/cne.21220","article-title":"Morphological and physiological properties of parvalbumin- and calretinin-containing gamma-aminobutyric acidergic neurons in the substantia nigra","volume":"500","author":"Lee","year":"2007","journal-title":"J Comp. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1016\/j.celrep.2019.04.068","article-title":"Synergistic Nigral Output Pathways Shape Movement","volume":"27","author":"Rizzi","year":"2019","journal-title":"Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113287","DOI":"10.1016\/j.celrep.2023.113287","article-title":"Targeting parvalbumin-expressing neurons in the substantia nigra pars reticulata restores motor function in parkinsonian mice","volume":"42","author":"Mallet","year":"2023","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1126\/science.aaz0956","article-title":"A common hub for sleep and motor control in the substantia nigra","volume":"367","author":"Liu","year":"2020","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/acn3.381","article-title":"Red hair, MC1R variants, and risk for Parkinson\u2019s disease\u2014A meta-analysis","volume":"4","author":"Chen","year":"2017","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/pcmr.12090","article-title":"The masters talk: The PGC-1\u03b1\u2013MITF axis as a melanoma energizer","volume":"26","author":"Ronai","year":"2013","journal-title":"Pigm. Cell Melanoma R."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4404","DOI":"10.1002\/jcb.26094","article-title":"PGC-1\u03b1 in Melanoma: A Key Factor for Antioxidant Response and Mitochondrial Function","volume":"118","author":"Abrisqueta","year":"2017","journal-title":"J. Cell. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"522","DOI":"10.7150\/thno.49426","article-title":"Melanocortin 1 receptor attenuates early brain injury following subarachnoid hemorrhage by controlling mitochondrial metabolism via AMPK\/SIRT1\/PGC-1\u03b1 pathway in rats","volume":"11","author":"Xu","year":"2021","journal-title":"Theranostics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0169-328X(02)00696-4","article-title":"Pivotal role of attractin in cell survival under oxidative stress in the zitter rat brain with genetic spongiform encephalopathy","volume":"111","author":"Muto","year":"2003","journal-title":"Mol. Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1016\/j.neurobiolaging.2006.06.014","article-title":"The neuroprotective role of attractin in neurodegeneration","volume":"28","author":"Paz","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.neulet.2008.10.059","article-title":"Chronic treatment with melatonin attenuates serotonergic degeneration in the striatum and olfactory tubercle of zitter mutant rats","volume":"448","author":"Ueda","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1007\/s00441-021-03423-w","article-title":"Attractin deficiency causes metabolic and morphological abnormalities in slow-twitch muscle","volume":"384","author":"Ehara","year":"2021","journal-title":"Cell Tissue Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ahmad, R. (2016). The Role of Attractin in Neurodegeneration Caused by Oxidative Stress. Free Radicals and Diseases, IntechOpen.","DOI":"10.5772\/61358"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jchemneu.2015.12.011","article-title":"Alterations of neurochemical expression of the coeliac-superior mesenteric ganglion complex (CSMG) neurons supplying the prepyloric region of the porcine stomach following partial stomach resection","volume":"72","author":"Palus","year":"2016","journal-title":"J. Chem. Neuroanat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1002\/cne.21909","article-title":"\u201cFast\u201d plasma membrane calcium pump PMCA2a concentrates in GABAergic terminals in the adult rat brain","volume":"512","author":"Burette","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"103650","DOI":"10.1016\/j.mcn.2021.103650","article-title":"Parvalbumin subtypes of cerebellar Purkinje cells contribute to differential intrinsic firing properties","volume":"115","author":"Brandenburg","year":"2021","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8864100","DOI":"10.1155\/2020\/8864100","article-title":"Activation of the Melanocortin-1 Receptor by NDP-MSH Attenuates Oxidative Stress and Neuronal Apoptosis through PI3K\/Akt\/Nrf2 Pathway after Intracerebral Hemorrhage in Mice","volume":"2020","author":"Fu","year":"2020","journal-title":"Oxidative Med. Cell. Longev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/236\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:56:42Z","timestamp":1760115402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/236"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,30]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ijms26010236"],"URL":"https:\/\/doi.org\/10.3390\/ijms26010236","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,30]]}}}