title: Dietary energy intake modifies brainstem autonomic dysfunction caused by mutant α-synuclein.
abstract: Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of α-synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of α-synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of α-synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of α-synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Griffioen
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Rothman
authors.forename: Bruce
authors.initials: B
authors.lastname: Ladenheim
authors.forename: Ruiqian
authors.initials: R
authors.lastname: Wan
authors.forename: Neil
authors.initials: N
authors.lastname: Vranis
authors.forename: Emmette
authors.initials: E
authors.lastname: Hutchison
authors.forename: Eitan
authors.initials: E
authors.lastname: Okun
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D001933:Brain Stem / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D002149:Energy Intake; D006339:Heart Rate; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: C497605:Snca protein, mouse; D051844:alpha-Synuclein