Role of LRP10 in Parkinson's disease and dementia: a knockout mouse model - Project Summary/Abstract Parkinson's disease (PD), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB) are the common neurodegenerative disorders severely affecting the aging population worldwide. PD is recognized as the most common neurodegenerative movement disorder. Up to 80% of individuals with PD develop cognitive impairment which progresses into overt dementia, leading to a diagnosis of PDD. DLB accounts for roughly 5% of dementia cases in elderly people and is associated with severe and widespread pathological findings of Lewy bodies in the brain, followed by parkinsonism in over 85% of cases. Most patients with PD, PDD and DLB do not carry mutations in known disease-causing genes. Recently, loss-of-function variants in the low- density lipoprotein receptor-related protein 10 (LRP10) gene have been associated with PD, PDD, and DLB. How its loss-of-function is mechanistically involved in the pathogenesis of PD, PDD and DLB and what is the physiological and pathological role of LRP10 remain largely unknown. No LRP10 animal models have been developed and characterized. We propose to generate and characterize the first LRP10 knockout (KO) mouse model. Our preliminary data shows that LRP10 KO mice exhibit both locomotor and cognitive function deficits and develop a-Synuclein (aSyn) and tau pathology. Proteomic analysis and immunoprecipitation (IP) pulldown revealed potential LRP10 targets/ interactors. Based on these observations, our hypothesis is that the loss of LRP10 function causes PD and dementia, which acts through LRP10-specific targets. To test this hypothesis, we will examine neuroinflammation, synaptic dysfunction, neurodegeneration, and associated cellular and behavioral deficits with aging in LRP10 KO mice and determine the potential underlying molecular mechanisms. We anticipate that our work will provide insights in LRP10 physiological functions and pathological roles, and further provide a common mechanism for the Lewy body disorders (PD, PDD and DLB) in general.
