Platform presentation—Early Defect of Transforming Growth Factor β1 Formation in Huntington's Disease

Abstract

Background Huntington's disease (HD) is a neurodegenerative disease due to an abnormal accumulation of mutated huntingtin with toxic effects in cortical and subcortical brain areas. Neuropathological studies have demonstrated an increased reactivity of astrocytes and oligodendroglial cells in striatum and cortex. Activation of astrocytes and microglia, which reflects a process of neuroinflammation, is already observed during the presymptomatic stage of HD. Activated astrocytes and microglia critically regulate processes of neuronal death and survival by secreting glutamate, neurotrophic factors, and pro- and anti-inflammatory cytokines. Methods We used two transgenic animal models of HD (R6/2 and YAC128 mice), HD mouse and human brain samples and controls, cell line cultures (astrocytes cell lines and striatal knock-in cell lines), and blood serum from HD subjects. Results Immunohistochemical analysis of brain cortex from human HD and biochemical analysis of human serum showed a reduction of TGFB1 levels in presymptomatic subjects, which correlate with decreased brain glucose metabolism and loss of white matter volume as assessed by nuclear magnetic resonance image analysis. TGFB1 levels increased with the progression of disease up to the late phase of disease, being linearly associated with worsening of motor clinical scores and progression rate. As the production of TGFB1 by glial cells is under the control of mGlu3 metabotropic glutamate receptors and activation of glial mGlu3 receptors is neuroprotective via a paracrine mechanism mediated by TGFB1, we examined the ability of mGlu2/3 receptor agonists to regulate brain TGFB1 levels in mouse models of HD. Biochemical analysis of TGFB1 levels showed an increase of TGFB1 levels in the striatum of wild-type mice, whereas no increase was observed in presymptomatic and symptomatic R6/2 mice. Conclusions These data suggest that TGFB1 production could be defective in the HD brain and this could contribute to the pathophysiology of neuronal death in HD.