Abstract
Parkinson’s disease is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, pathological accumulation of alpha-synuclein and motor symptoms, but also by non-motor symptoms. Metabolic abnormalities including body weight loss have been reported in patients and could precede by several years the emergence of classical motor manifestations. However, our understanding of the pathophysiological mechanisms underlying body weight loss in PD is limited. The present study investigated the links between alpha-synuclein accumulation and energy metabolism in transgenic mice overexpressing Human wild-type (WT) alpha-synuclein under the Thy1 promoter (Thy1-aSYN mice). Results showed that Thy1-aSYN mice gained less body weight throughout life than WT mice, with significant difference observed from 3 months of age. Body composition analysis of 6-month-old transgenic animals showed that body mass loss was due to lower adiposity. Thy1-aSYN mice displayed lower food consumption, increased spontaneous activity, as well as a reduced energy expenditure compared to control mice. While no significant change in glucose or insulin responses were observed, Thy1-aSYN mice had significantly lower plasmatic levels of insulin and leptin than control animals. Moreover, the pathological accumulation of alpha-synuclein in the hypothalamus of 6-month-old Thy1-aSYN mice was associated with a down-regulation of the phosphorylated active form of the signal transducer and activator of transcription 3 (STAT3) and of Rictor (the mTORC2 signaling pathway), known to couple hormonal signals with the maintenance of metabolic and energy homeostasis. Collectively, our results suggest that (i) metabolic alterations are an important phenotype of alpha-synuclein overexpression in mice and that (ii) impaired STAT3 activation and mTORC2 levels in the hypothalamus may underlie the disruption of feeding regulation and energy metabolism in Thy1-aSYN mice.
Highlights
Parkinson’s disease (PD) is the most common movement neurodegenerative disorder in elderly adults
We found that alphasynuclein, detected with an antibody that recognizes both mouse and Human proteins, was expressed in the hypothalamus at a level comparable to that observed in the substantia nigra and the striatum in 6-month-old Thy1-aSYN mice (Figure 6A)
Our results show no change in blood glucose levels and insulinemia and a non-statically decrease of the plasmatic levels of leptin in 3-month-old Thy1-aSYN mice compared to controls (2416 ± 699 vs. 6273 ± 1670 pg/ml; p = 0.1004) (Figure 7A)
Summary
Parkinson’s disease (PD) is the most common movement neurodegenerative disorder in elderly adults. It is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra and by the pathological accumulation of intraneuronal aggregated and hyperphosphorylated alphasynuclein in Lewy bodies (Bridi and Hirth, 2018). Missense mutations and multiplication of the gene encoding alphasynuclein SNCA (synuclein, alpha [non-A4 component of amyloid precursor]) were identified as genetic abnormalities associated with rare familial forms of PD (Polymeropoulos et al, 1997; Singleton et al, 2003; Chartier-Harlin et al, 2004; Ibanez et al, 2004). Polymorphisms regulating SNCA levels were subsequently associated with sporadic PD (Maraganore et al, 2006; Simon-Sanchez et al, 2009), supporting that alphasynuclein level is instrumental in most forms of the disease. It is generally accepted that these motor symptoms appear only after a substantial proportion of dopaminergic neurons are lost (Bezard et al, 2001)
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