Administrative Supplement to Molecular Segregation of Parkinson’s Disease by Patient-derived Neurons

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Summary Dementia is an age-dependent co-morbidity of Parkinson’s disease (PD) that affects up to 80% of PD patients. There is very little mechanistic understanding of PD Dementia (PDD), which together with Dementia with Lewy Body (DLB), constitute Lewy Body Dementia (LBD). The lack of a suitable model system significantly hampers the study of this complex disorder, which shares many features with Alzheimer’s disease (AD). In our preliminary study, we developed a method to differentiate induced pluripotent stem cells (iPSCs) to cortical neurons. Comparing cortical neurons derived from normal subjects and sporadic Alzheimer’s disease patients, we found significant increases in TAU phosphorylation and significant decreases in the expression of synaptic genes. In our parental R01 grant, we have developed a method to differentiate iPSCs to A9 dopaminergic (DA) neurons. In midbrain DA neurons derived from normal subjects and idiopathic PD patients, we have found significant differences in the expression of genes handling dopamine. Premised on these findings, we hypothesize that iPSC-derived cortical neurons and A9 dopaminergic neurons from LBD patients may exhibit molecular and cellular features that are significantly different from those of normal subjects. Three specific aims will be addressed to test the hypothesis, which extends the parental R01 grant to dementia in this administrative supplement application. We will generate cortical neurons (Aim 1) and A9 DA neurons (Aim 2) from iPSCs of LBD patients and normal subjects to examine the phosphorylation and aggregation states of TAU and -synuclein, and compare the global gene expression profile. We will confirm key findings in postmortem tissues from middle temporal cortex and substantia nigra of LBD patients and normal subjects (Aim 3). Information generated in this focused study will lay the foundation for discovery of LBD biomarkers using patient-derived neurons. Key targets identified in the study can be validated in drug discovery efforts to address cognitive, memory and motor symptoms of LBD using patient-derived cortical neurons or A9 DA neurons. The administrative supplement application will move the field forward by identifying molecular and cellular features that distinguish LBD from normal subjects in patient-derived neurons and postmortem tissues.