Cell Biology Of Genetic Neurodegenerative Disorders

Aging

Investigators

Linked publications, trials & patents

Abstract

In the period covered by this report, we have followed two major pieces of our work on the molecular and cell biology of inherited Parkinson disease (PD).[unreadable] [unreadable] We have continued to examine how mutations in recessive genes leading to parkinsonism, DJ-1 and PINK1, cause cell death. In work that has recently been submitted for publication, we have identified an oxidative-stress responsive RNA binding activity for DJ-1, a protein that has so far had no characterized function. Our work shows that several aspects of the function of this protein, in maintaining mitochondrial viability, modulating cell survival pathways and maintaining antioxidant status are most readily explained byt the single biochemical activity of RNA binding. We have also explored how mutations in a mitochondrial kinase, PINK1, affect mitochondrial morphology and function in living cells, again under oxidative conditions.[unreadable] [unreadable] Most of our work over the past year has been aimed at expanding our previously published studies showing that a dominant gene for Parkinson's disease, LRRK2, is toxic to neurons when mutated. We had shown that some mutations in LRRK2 trigger cell death by virtue of increased kinase activity. However, we also found that some mutations outside of the kinase domain are equally toxic and trigger cell death in a kinase-dependent manner without apparently increasing kinase activity in vitro. In the past year we have shown that these mutations work by slowing GTPase activity of the protein in complex, which will leave the kinase in a higher activity state for longer than the wild type protein. We have also shown that the mutations cannot be placed into a related kinase, LRRK1, and cause the same toxic effect. Our aggregate data clearly support the hypothesis that kinase activity is a promising therapeutic target for Parkinson's disease.