Define molecular events driving selective neuronal death in multiple neurodegenerative diseases by snRNA-seq

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Project Summary Despite decades of research, currently the mechanisms of neurodegeneration in Alzheimer’s disease (AD) and Parkinson Disease (PD) remain controversial and there are no therapies can prevent, slow, or halt disease progression. Neurodegenerative diseases have two fundamental general characteristics. 1) The pathology associated with the disease only affects particular neurons (‘selective neuronal vulnerability’); 2) The pathology worsens with time and impacts more regions in a stereotypical and predictable fashion. The discovery of key pathways that regulate this differential susceptibility of neurons to degeneration holds great potential for the discovery of novel drug targets and the development of promising neuroprotective treatment strategies. However, the mechanisms underlying selective neuronal and regional vulnerability have been difficult to dissect because of our limited ability to distinguish different neuronal subpopulations. Loss of dopaminergic neurons in the SN is a hallmark of PD which underlies the parkinsonian motor symptoms such as rigidity and tremor. Neuronal loss also occurs in the SN of AD [8, 9], however, often without co-occurring parkinsonian motor symptoms. Dopaminergic neurons within the SN are highly heterogeneous [10] and the loss of the dopaminergic neurons in PD is heterogeneous across different axes [11-14]. It is unclear whether the same population of neurons were lost in AD and PD and whether the mechanisms of neuronal loss are shared between the two diseases. Neuroinflammation - activation of the neuroimmune cells (e.g. microglia) into proinflammatory states - are shared pathological contributors in AD and PD. However, the molecular identity of different microglia subpopulations and the role of neuroinflammation in the selective neuronal death remain unclear. Therefore, we propose to use single nucleus RNA-seq (snRNA-seq), an unbiased approach to identify and characterize distinct cell populations in tissues, to dissect the mechanisms underlying selective neuronal death. Specifically, our specific aims are: Aim 1: Characterize and validate cellular heterogeneity, cellular and transcriptomic changes of neuron and microglia from the SN brain tissues of AD, PD patients and age-matched controls. Aim 2: Dissect the mechanisms of cell composition and transcriptome dysregulation in AD and PD. Our study will provide 1) molecular markers and tools for targeted neuronal and microglia subpopulation isolation and manipulation; 2) better understanding of the dynamic change of different neuronal and microglia subpopulation, their transcriptomic changes and the putative regulatory mechanisms in AD and PD; 3) high- confidence new candidate genes and pathways as targets to develop effective immunotherapies or neuroprotective strategies.