Grant: Project Grant

Brain circuits and cells stop working properly before the cell death that characterizes the end point of many brain diseases. Working out how this dysfunction is caused, and reversing it, may provide treatments that stop the progression to dead brain cells. Synaptic networks are altered in early stages of Parkinson's disease (PD), producing early symptoms that reduce quality of life and signal the progression of disease. Mutations in the protein LRRK2 are the highest gene risk for PD, and produce a typical disease profile. LRRK2 is a kinase enzyme; LRRK2 kinase hyperactivity is produced by the disease mutations and there is evidence this also happens in non-familial PD. Inhibitor drugs against LRRK2 kinase activity are in people for early clinical safety trials, but our understanding of LRRK2 biology and the effects of inhibition on brain circuits and cells is poor. Like LRRK2, mutations in a second protein VPS35 also cause typical PD. VPS35 recycles brain proteins, avoiding their disposal, and evidence shows VPS35 mutations may cause dysfunction via LRRK2. We study mice with LRRK2 or VPS35 mutations. They both have early alterations to brain circuits, that we can reverse with LRRK2 inhibitors. However, as they age, changes to their neural circuits become more serious. Although mutation effects seem to be undone in young mice (arguing LRRK2 inhibition is protective if given very early), we don't know if the drugs will help older animals, at ages that correlate to when people are diagnosed in the clinic. We will test if the inhibitors reverse changes in old mice, and whether the drugs can prevent the progression to severe changes if given early. We will also learn more about what the drugs do to normal mice. If the drugs work for LRRK2 and VPS35 mutations, this suggests they have clinical value for more than one type of PD. Our results will provide safety and efficacy information for developing clinical trials, and potentially guide novel interventions.