Investigator, Asst Prof (M) Neurology, Mass General Research Institute

Assistant Professor of Neurology Harvard Medical School

crystallins; endosomes; htt proteolysis; huntingtin; huntington disease; hypertonic solutions; lysosomes; nerve tissue proteins; nuclear proteins; peptides; phosphoinositol phosphates; phospholipids; rab gtp-binding proteins

Dr. Kegel studies the normal and altered function of huntingtin (htt), the protein mutated in Huntington Disease (HD).  Her early work revealed that autophagy and the lysosomal system were activated with htt accumulation in an HD cell system.

More recently, she has discovered a normal association of htt with specific phosphoinositol phosphates (PIPs). PIPs are lipids present in membranes that can act to target proteins to specific sites within cells.

The finding that htt interacts with specific PIPs will direct investigations that will enable us to elucidate htt function at a molecular level. Different PIPs are generated by growth factor molecules such as IGF1, PDFG, and EGF to propagate signals regulating survival and changes in cellular morphology.

Specific PIPs are also used to regulate various steps of intracellular membrane trafficking pathways. Experiments addressing the mechanism, regulation and consequences of htt-PIP interactions are currently being pursued.

Dr. Kegel also has expertise in drug discovery for HD. An important goal of her work is to establish a mouse embryonic stem cell model of HD for translational research In collaboration with other investigators, small cell-permeable molecules capable of inhibiting htt proteolysis, a process thought to initiate HD pathology, are being identified.