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) a-synuclein (AS). To study if diet-induced obesity could be an environmental risk factor for PD-related a-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 glucoseintolerant, 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 a-synucleinopathy as detected by immunostaining with antibodies against pathology-associated pS129. Amyloidlike 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 a-synucleinopathies. The molecular and cellular mechanisms remain to be further elucidated.

Impact of intermittent fasting on health and disease processes

“…Maintenance of the α-synuclein mutant mice on ADF reversed the autonomic deficit, whereas a high fat diet exacerbated the autonomic deficit (Griffioen et al, 2013). Consistent with the latter findings, a high fat diet hastened the onset of motor dysfunction and brainstem pathology in another line of α-synuclein mutant mice, which was associated with reduced activity of kinases known to be involved in neurotrophic factor signaling (Rotermund et al, 2014). In addition to enhancement of neurotrophic factor/BDNF signaling, IF may counteract PD-related pathogenic processes by stimulating autophagy.…”

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

“…Insulin resistance has been proposed to contribute to neurodegenerative diseases via a number of mechanisms, including promotion of disease-specific pathological lesions and an increase in neuronal vulnerability and neurodegeneration in general 194 . Many T2DM animal model studies have supported this concept that T2DM promotes the development and accumulation of ADRD pathologies, such as amyloid-β plaques, tau phosphorylation and neurofibrillary lesions 195 , and α-synuclein lesions 196 .…”

Obesity and ageing: Two sides of the same coin

“…At the anatomical level, results from the cortical reconstruction of 527 individuals have revealed that excess adiposity is associated with cerebral white‐matter atrophy corresponding to a 10‐year older brain in people with obesity . Obesity may accelerate the onset of neurodegenerative phenotypes through the aggregation of α‐synuclein, pathological protein modifications, and neuroinflammation in mice . In humans, α‐synuclein also accumulates with age in brain; this accumulation not only accelerates the onset of Parkinson disease but also interacts with free fatty acid (FFA) in people with obesity and hyperlipidaemia .…”