Hugo Bellen

Seminar Details

Host: Dr. Dzmitry Kurouski

Time: 4:00 pm-5:00 pm

Location: BICH 108

Seminar Abstract

One of the main aims of our research is to elucidate the molecular basis of neurodegeneration. We discovered a dramatic increase in Lipid Droplets (LD) in glial cells (pigment cells) in a number of mutants that affect mitochondrial proteins. These mutants exhibit elevated ROS and accumulate peroxidated lipids in glia. Elevated ROS in neurons triggers c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP) activity, leading to the synthesis of lipids. These lipids are peroxidated and shuttled to glia to form LD,  lowering ROS in neurons and delaying neurodegeneration. This phenomenon is evolutionarily conserved. The neuronally produced lipids are transferred to extracellular apolipoproteins like ApoD and ApoE, which are critical for glial LD formation.  We therefore tested the role of Alzheimer Disease (AD) risk genes and showed that several of these genes/proteins impact neuroprotective LD formation, including homologs of human ABCA1, ABCA7, VLDLR, VPS26, VPS35, AP2A, PICALM, and CD2AP. We also discovered that endogenous Tau is required for glial LD formation. Hence, this research has revealed a pathway that plays an important role in AD. 

We also embarked on the study of iPLA2-VIA, a gene whose loss causes infantile neuroaxonal dystrophy (early death) and parkinsonism (PD). Loss of the fly homolog, PLA2G6, reduces lifespan, impairs synaptic transmission, and causes the demise of the neurons. Phospholipases typically hydrolyze glycerol phospholipids, but loss of iPLA2-VIA does not affect phospholipid composition in the brain but rather causes an elevation in ceramides. Loss of PLA2G6 causes a progressive loss of retromer function and leads to a deficit in the recycling of proteins and membranes from endosomes to plasma membrane, thereby increasing trafficking from the endosome to the lysosome. This leads to a progressive lysosomal expansion and ceramide accumulation. We argue that the lysosomal-ceramide metabolism pathway is an important player in the pathology of PD.