title: Diet-induced obesity accelerates the onset of terminal phenotypes in α-synuclein transgenic mice.
abstract: Parkinson's disease (PD) and diabetes belong to the most common neurodegenerative and metabolic syndromes, respectively. Epidemiological links between these two frequent disorders are controversial. The neuropathological hallmarks of PD are protein aggregates composed of amyloid-like fibrillar and serine-129 phosphorylated (pS129) α-synuclein (AS). To study if diet-induced obesity could be an environmental risk factor for PD-related α-synucleinopathy, transgenic (TG) mice, expressing the human mutant A30P AS in brain neurons, were subjected after weaning to a lifelong high fat diet (HFD). The TG mice became obese and glucose-intolerant, as did the wild-type controls. Upon aging, HFD significantly accelerated the onset of the lethal locomotor phenotype. Coinciding with the premature movement phenotype and death, HFD accelerated the age of onset of brainstem α-synucleinopathy as detected by immunostaining with antibodies against pathology-associated pS129. Amyloid-like neuropathology was confirmed by thioflavin S staining. Accelerated onset of neurodegeneration was indicated by Gallyas silver-positive neuronal dystrophy as well as astrogliosis. Phosphorylation of the activation sites of the pro-survival signaling intermediate Akt was reduced in younger TG mice after HFD. Thus, diet-induced obesity may be an environmental risk factor for the development of α-synucleinopathies. The molecular and cellular mechanisms remain to be further elucidated. Life-long high fat diet (HFD) induces obesity and glucose intolerance in a transgenic mouse model for α-synucleinopathy and thereby leads to decreased life span as well as accelerated age of onset of the terminal phenotype. This is accompanied by increased neuroinflammation and premature α-synuclein pathology in the brainstems of the HFD-fed mice.
authors.affiliation: German Center of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Rotermund
authors.forename: Felicia M
authors.initials: FM
authors.lastname: Truckenmüller
authors.forename: Heinrich
authors.initials: H
authors.lastname: Schell
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
mesh_terms: D000821:Animal Feed; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D010641:Phenotype; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C497605:Snca protein, mouse; D051844:alpha-Synuclein
keywords: Parkinson's disease; diabetes; high fat diet; synuclein; transgenic mice