Neurociencias

Mitochondrial dysfunction, in particular at the level of complex I of the mitochondria respiratory chain, has long been implicated in the pathogenesis of PD. However, a primary direct pathogenic role of complex I deficiency in PD-related neurodegeneration remains to be elucidated. Some of our current research projects are aimed at determining the cause and role of mitochondrial alterations in PD.

Programmed cell death (PCD), a physiological process that occurs naturally during development in which molecular programs intrinsic to the cell are activated to cause its own destruction, is inappropriately re-activated in PD, causing SNpc dopaminergic neurodegeneration. We are currently exploring the mechanisms that activate and regulate PCD pathways in PD in order to identify new molecular targets of potential therapeutic significance to attenuate or prevent dopaminergic neurodegeneration.

From a neuropathological point of view, PD is characterized not only by the loss of nigrostriatal dopaminergic neurons but also by the presence in affected brain region of intraneuronal proteinacious cytoplasmic inclusions, called Lewy bodies (LB). However, the mechanisms of formation and significance of LB to the disease process remains to be elucidated. Our group is currently studying the potential involvement of lysosomal- and proteasomal-mediated cellular degradation pathways on the formation of LB, as well as the mechanisms of spread of LB pathology.

In the past few years, mutations that cause familial forms of PD have been identified in several genes, including alpha-synuclein, parkin, DJ-1, PINK-1 and Dardarin/LRRK2. Exploring how these mutations lead to familial forms of PD should provide important clues to understanding the pathogenesis of the sporadic forms of the disease and allow the development of new genetic models of PD.

Autophagy is the degradation of intracellular components inside de lysosomes, is a highly conserved mechanism of quality control in the cells, and it is essential for the maintenance of cellular homeostasis and the control of an efficient cellular response to stress. Intracellular accumulation of altered and misfolded proteins is the basis of most neurodegenerative disorders; recent studies have shown that a primary failure in autophagy could be responsible for the accumulation of these altered proteins inside the affected neurons. Alterations in autophagy have been associated with Huntington’s disease. Preliminary results show a failure in macroautophagy, the main lysosomal pathway responsible for the degradationof cytosolic proteins and organelles. This failure can be compensated by the activation of other alternative proteolytic pathways that can degrade cytosolic soluble proteins; however the insoluble aggregates (one of the main hallmarks of this disease) and organelles remain inside the cell. The long term accumulation of undigested organelles, especially mitochondria, can be a new source of intracellular oxidative stress. Indeed, dysfunctional mitochondria and oxidative stress has already been described as major contributors to neuronal loss in Huntington’s disease and the deficient degradation of dysfunctional mitochondria by autophagy becomes an aggravating factor in the pathophysiology of this disease.The overall goal of the project is to study the failure of mitochondria turnover by autophagy (mitophagy) in Huntington´s disease. Identifying the role of huntingtin protein in autophagy and the molecular mechanism of its failure in Huntington’s disease would be essential for future efforts to restore proper autophagic activity and make sure that dysfunctional organelles will be properly eliminated.