PHD Student

KEY WORDS: neurodegeneration, selective neuronal vulnerability, spinocerebellar ataxia, single nucleus sequencing, targeted profiling, transcriptomic atlas of degenerating neurons

Principal Investigator: Pawel M. Switonski

Research topic: Elucidating neurodegenerative processes using direct profiling of selectively vulnerable neurons

I. Project description

Defined pattern of neurodegeneration is a common theme in most neurodegenerative disorders. It is a result of selective neuronal vulnerability - a phenomenon in which dysfunction and death affect only specific subpopulations of cells. A major obstacle in mechanistically understanding selective vulnerability is that the sensitive types of neurons constitute only a small fraction of all cells in the brain, which renders separation from other cellular populations difficult. Consequently, a dominant portion of scientific data is generated using bulk tissue profiling that averages out the signal from affected neurons.

This project seeks to identify cell type-unique molecular pathomechanisms using advanced cell type-specific profiling methods. A spinocerebellar ataxia type 7 (SCA7) transgenic mice (SCA7-266Q line) that exhibit progressive degeneration of cerebral Purkinje cells (PCs) will be used as a model of selective degeneration. We will evaluate genetically labeled PC nuclei from SCA7-266Q and wild-type littermates for differential gene expression using whole transcriptome RNA-seq. Simultaneously, we will use single-nucleus RNA/ATAC-seq to assess the cellular distribution, differential gene expression and accessible chromatin regions in all cellular subpopulations identified in SCA7-266Q mouse cerebella. Comparative functional analysis performed on the expression and epigenetic data from PC and control non-PC nuclei will deliver candidates for cellular networks predominantly altered in PCs. Finally, we will use a hypothesis-driven approach to determine if the alteration in the PARP1-NAD+-SIRT1-PGC-1alpha regulatory axis, recently discovered by us in SCA7 using bulk cerebellar tissue, can also explain degeneration of SCA7 PCs.

Cell-specific mechanisms of neurodegeneration are a largely unexplored area of research. The results of this project will significantly advance our understanding of selective neuronal vulnerability, for which there is currently no satisfactory explanation.

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