Huntington’s Disease is an inherited disease caused by the expansion of CAG trinucleotide, which results in translation of a protein containing an enlarged polyglutamine (polyQ) domain. HD is characterized by the progressive degeneration of neurons, resulting in involuntary movement and death. Neuronal cell death is caused by an excess of glutamate, that is maintained and physiological level by a non autonomous cycle between glia and neurons, also called the glutamate-glutamine cycle. Glutamate removal from the synaptic cleft by neuroglia is reduced in a mouse model of Huntington's disease (HD) and in HD patients, suggesting that glial cells actively participate in the survival of neuronal cells. Is possible to manipulate components of the glutamate-glutamine to ameliorate to neuronal death in HD? To answer this question we are taking advantage of a Drosophila model that has been successfully used to dissect the cellular and molecular events of neurodegenerative disorders including HD. Our preliminary data show that modulation of the enzyme GS1 that converts glutamate into glutamine, in Drosophila’s neurons expressing the human mutant HttQ93, ameliorate animal motility and reduces neuronal loss in the adults. On the contrary, using enzymes that increase the concentration of glutamate has the opposite effect. Growth factor signaling play a dual role in the onset of HD and both in flies and mammals it was shown that while activation of IGF/Akt signaling in neuroglia ameliorates neuronal degeneration induced by HD, the opposite was seen when autophagy was inhibited by activation of the amino TOR signaling pathway. We are using genetics and biochemistry assays to better understand how components of the Insulin/ and TOR pathways act in the regulation of the glutamate-glutamine cycle, and in controlling autophagy in neuronal and glial cells. We are also analyzing if the expression of GS1 can ameliorate other polyQ induced-neuronal diseases such as the Spinocerebellar Ataxia 3 (SC3) to provide novel insights into the processes that cause neuronal degeneration not only in Huntington's disease but also in other neurodegenetive pathologies.
|Titolo:||Autophagy and glutamate signaling in the onset of Huntington’s Disease|
PASINI, MARIA ENRICA (Penultimo)
|Data di pubblicazione:||set-2015|
|Settore Scientifico Disciplinare:||Settore BIO/06 - Anatomia Comparata e Citologia|
|Citazione:||Autophagy and glutamate signaling in the onset of Huntington’s Disease / L. Vernizzi, M.S. Figueiredo, M. Raneli, C. Paiardi, M.E. Pasini, P. Bellosta. ((Intervento presentato al 56. convegno Annual Drosophila Conference tenutosi a Heidelberg nel 2015.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|