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Despite that, fatigue has been under-recognized as symptom, its pathophysiology remains poorly understood, and there is no adequate treatment so far. Parkinson\u2019s disease is characterized by the progressive loss of midbrain dopaminergic neurons, eliciting the classical motor symptoms including slowing of movements, muscular rigidity and resting tremor. The dopamine synthesis is mediated by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin as a mandatory cofactor. Here, we showed that reserpine administration (1\u2009mg\/kg, two intraperitoneal injections with an interval of 48\u2009h) in adult Swiss male mice (8\u201310\u2009weeks; 35\u201345\u2009g) provoked striatal depletion of dopamine and tetrahydrobiopterin, and intolerance to exercise. The poor exercise performance of reserpinized mice was not influenced by emotional or anhedonic factors, mechanical nociceptive thresholds, electrocardiogram pattern alterations or muscle-impaired bioenergetics. The administration of levodopa (100\u2009mg\/kg; i.p.) plus benserazide (50\u2009mg\/kg; i.p.) rescued reserpine-induced fatigability-like symptoms and restored striatal dopamine and tetrahydrobiopterin levels. Remarkably, it was observed, for the first time, that impaired blood dopamine metabolism inversely and idependently correlated with fatigue scores in eighteen idiopathic Parkinson\u2019s disease patients (male n\u2009=\u200913; female n\u2009=\u20095; age 61.3\u2009\u00b1\u20099.59\u2009years). Altogether, this study provides new experimental and clinical evidence that fatigue symptoms might be caused by the impaired striatal dopaminergic neurotransmission, pointing to a central origin of fatigue in Parkinson\u2019s disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcab116","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T20:04:59Z","timestamp":1623096299000},"source":"Crossref","is-referenced-by-count":19,"title":["Impaired dopamine metabolism is linked to fatigability in mice and fatigue in Parkinson\u2019s disease patients"],"prefix":"10.1093","volume":"3","author":[{"given":"D\u00e9bora da Luz","family":"Scheffer","sequence":"first","affiliation":[{"name":"LABOX, Departamento de Bioqu\u00edmica, Centro de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Santa Catarina, Florian\u00f3polis, SC 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando Cini","family":"Freitas","sequence":"additional","affiliation":[{"name":"Graduate Program in Medical Sciences, University Hospital, Universidade Federal de Santa Catarina, Florian\u00f3polis, SC 88040-900, Brazil"},{"name":"Neurology Division, Hospital Governador Celso Ramos, Florian\u00f3polis, SC 88015-270, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aderbal Silva","family":"Aguiar Jr","sequence":"additional","affiliation":[{"name":"LABOX, Departamento de Bioqu\u00edmica, Centro de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Santa Catarina, Florian\u00f3polis, SC 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Ward","sequence":"additional","affiliation":[{"name":"Kirby Neurobiology Center, Boston Children\u2019s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz Guilherme Antonacci","family":"Guglielmo","sequence":"additional","affiliation":[{"name":"Departamento de Educa\u00e7\u00e3o F\u00edsica, Centro de Desportos, Universidade Federal de Santa Catarina, Florian\u00f3polis, SC 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui Daniel","family":"Prediger","sequence":"additional","affiliation":[{"name":"Departamento de Farmacologia, Centro de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Santa Catarina, Florian\u00f3polis, SC 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane J F","family":"Cronin","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biotechnology of the Austrian Academy of Sciences, A-1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Walz","sequence":"additional","affiliation":[{"name":"Graduate Program in Medical Sciences, University Hospital, Universidade Federal de Santa Catarina, Florian\u00f3polis, SC 88040-900, Brazil"},{"name":"Center for Applied Neuroscience, University Hospital, Universidade Federal de Santa Catarina, Florian\u00f3polis, SC 88040-900, Brazil"},{"name":"Neurology Division, Departament of Internal Medicine, University Hospital, Universidade Federal de Santa Catarina, Florian\u00f3polis, SC 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick A","family":"Andrews","sequence":"additional","affiliation":[{"name":"Kirby Neurobiology Center, Boston Children\u2019s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"The Salk in Institute for Biological Studies, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Latini","sequence":"additional","affiliation":[{"name":"LABOX, Departamento de Bioqu\u00edmica, Centro de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Santa Catarina, Florian\u00f3polis, SC 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