Distinct region-specific alpha-synuclein oligomers in A53T transgenic mice: implications for neurodegeneration.

Aggregation of alpha-synuclein (alpha-syn), a process that generates oligomeric intermediates, is a common pathological feature of several neurodegenerative disorders. Despite the potential importance of the oligomeric alpha-syn intermediates in neuron function, their biochemical properties and pathobiological functions in vivo remain vastly unknown. Here we used two-dimensional analytical separation and an array of biochemical and cell-based assays to characterize alpha-syn oligomers that are present in the nervous system of A53T alpha-syn transgenic mice. The most prominent species identified were 53 A detergent-soluble oligomers, which preceded neurological symptom onset, and were found at equivalent amounts in regions containing alpha-syn inclusions as well as histologically unaffected regions. These oligomers were resistant to SDS, heat, and urea but were sensitive to proteinase-K digestion. Although the oligomers shared similar basic biochemical properties, those obtained from inclusion-bearing regions were prominently reactive to antibodies that recognize oxidized alpha-syn oligomers, significantly accelerated aggregation of alpha-syn in vitro, and caused primary cortical neuron degeneration. In contrast, oligomers obtained from non-inclusion-bearing regions were not toxic and delayed the in vitro formation of alpha-syn fibrils. These data indicate that specific conformations of alpha-syn oligomers are present in distinct brain regions of A53T alpha-syn transgenic mice. The contribution of these oligomers to the development of neuron dysfunction appears to be independent of their absolute quantities and basic biochemical properties but is dictated by the composition and conformation of the intermediates as well as unrecognized brain-region-specific intrinsic factors.

Strain-specific Differences in the Effects of Lymphocytes on the Development of Insulin Resistance and Obesity in Mice.

Obesity is characterized as a chronic, low-grade inflammatory disease owing to the infiltration of the adipose tissue by macrophages. Although the role of macrophages in this process is well established, the role of lymphocytes in the development of obesity and metabolism remains less well defined. In the current study, we fed WT and Rag1-/- male mice, of C57BL/6J and BALB/c backgrounds, high-fat diet (HFD) or normal diet for 15 wk. Compared with WT mice, Rag1-/- mice of either of the examined strains were found less prone to insulin resistance after HFD, had higher metabolic rates, and used lipids more efficiently, as shown by the increased expression of genes related to fatty acid oxidation in epidydimal white adipose tissue. Furthermore, Rag1-/- mice had increased Ucp1 protein expression and associated phenotypic characteristics indicative of beige adipose tissue in subcutaneous white adipose tissue and increased Ucp1 expression in brown adipose tissue. As with inflammatory and other physiologic responses previously reported, the responses of mice to HFD show strain-specific differences, with increased susceptibility of C57BL/6J as compared with BALB/c strain. Our findings unmask a crucial role for lymphocytes in the development of obesity and insulin resistance, in that lymphocytes inhibit efficient dissipation of energy by adipose tissue. These strain-associated differences highlight important metabolic factors that should be accommodated in disease modeling and drug testing.

CD8+ T cells in beige adipogenesis and energy homeostasis.

Although accumulation of lymphocytes in the white adipose tissue (WAT) in obesity is linked to insulin resistance, it remains unclear whether lymphocytes also participate in the regulation of energy homeostasis in the WAT. Here, we demonstrate enhanced energy dissipation in Rag1-/- mice, increased catecholaminergic input to subcutaneous WAT, and significant beige adipogenesis. Adoptive transfer experiments demonstrated that CD8+ T cell deficiency accounts for the enhanced beige adipogenesis in Rag1-/- mice. Consistently, we identified that CD8-/- mice also presented with enhanced beige adipogenesis. The inhibitory effect of CD8+ T cells on beige adipogenesis was reversed by blockade of IFN-γ. All together, our findings identify an effect of CD8+ T cells in regulating energy dissipation in lean WAT, mediated by IFN-γ modulation of the abundance of resident immune cells and of local catecholaminergic activity. Our results provide a plausible explanation for the clinical signs of metabolic dysfunction in diseases characterized by altered CD8+ T cell abundance and suggest targeting of CD8+ T cells as a promising therapeutic approach for obesity and other diseases with altered energy homeostasis.