PATHOLOGICAL DISTURBANCES OF MEMBRANE DYNAMICS

Lipid composition is frequently altered in disease states but the biophysical implications of these changes on the pathophysiology are underexplored. In our group we investigate how the biophysical properties of biological membranes are affected by different pathological conditions. We are particularly interested in Gaucher Disease (GD) and Niemman-Pick type C1 Disease (NPC1), two LSDs known for their impaired lipid metabolism. These diseases are characterized by the primary accumulation of glucosylceramide (GlcCer), and cholesterol and sphingosine (Sph), respectively, in the lysosomes. This lipid accumulation has major pathophysiological consequences, some of which related to altered lipid/protein trafficking, plasma membrane-receptors recycling and lipid synthesis – cellular events that depend on the biophysical properties of the membranes. Our studies aim therefore to address the biophysical implications of lipid accumulation in GD and NPC1, ultimately contributing to the identification of molecular mechanisms underlying the pathophysiology of these diseases.

EXPLORING THE BIOPHYSICAL LINK BETWEEN GAUCHER DISEASE AND PARKINSON’S DISEASE

Mutations in GBA1 are the most important genetic risk factor for developing Parkinson’s disease (PD), but also the cause of Gaucher Disease (GD), the most common lysosomal storage disease. GBA1 encodes the lysosomal hydrolase acid-beta-glucosidase (GCase), an enzyme involved in sphingolipids metabolism. Defects in GCase cause lysosomal disfunction (LysD) due to accumulation of glucosylceramide (GlcCer) and glucosylsphingosine. The mechanisms linking GBA1 mutations to PD development remain elusive. It is suggested that accumulation of GlcCer, and altered sphingolipid levels, as observed in PD and GBA-PD (GBA1-mutation carrier PD), might affect membrane properties and dynamics, impairing diverse cellular events, including lysosomal function. In this project a multidisciplinary approach that combines biophysical studies, advanced imaging techniques, and state-of-the-art biochemical and cell biology methods will be used to identify the biophysical mechanisms underlying LysD observed in GD and PD, and to investigate if manipulation of membrane biophysical properties protects from neurodegeneration. These studies will provide new directions towards the identification of therapeutic targets and early disease biomarkers associated to these diseases.

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