Alzheimer’s disease (AD) and the related dementia, frontotemporal lobar degeneration (FTLD), share several key clinical and neuropathological features and have been considered as two ends of a disease spectrum. In support of this, genetic evidence shows that patients with dominant mutations in the Progranulin (GRN) gene invariably develop FTLD with TDP-43 proteinopathy, characterized by the accumulation of RNA binding protein TDP-43 in layers 2-3 of the frontal cortex. Interestingly, single nucleotide polymorphisms (SNPs) in the 3’UTR of the GRN gene reduce Progranulin (PGRN) protein levels and have been associated with increased risk of TDP- 43 proteinopathy in the limbic regions in 30-40% of AD patients. Despite these intriguing genotype-phenotype correlations, how PGRN deficiency promotes glial and neuronal pathology remains poorly understood. To investigate the mechanism of neurodegeneration in PGRN deficiency, we performed single-nuclei RNA- sequencing (snRNA-seq) in the thalamus of Grn-/- mice during the aging process and showed that, in PGRN deficiency, microglia are the first cell type to show progressive loss of homeostatic genes and acquire transcriptomic and histopathological features of a pro-inflammatory state that promotes neuronal cell death and TDP-43 proteinopathy. To connect these results with human disease, we’ve conducted a pilot study by comparing the results from snRNA-seq using postmortem tissues from the frontal cortex and thalamus of FTLD- GRN cases with those from similar brain regions in 19-month-old Grn-/- mice. This human-mouse snRNA-seq comparison revealed shared transcriptomic changes in FTLD-GRN cases and Grn-/- mice, including cellular responses in microglia (exocytosis, immune activation, and chemotaxis) and astrocytes (astrocyte-vascular coupling, cell adhesion, and synaptic organization) in both brain regions. Furthermore, our results uncovered transcriptomic changes in excitatory and inhibitory neurons in the frontal cortex and thalamus of FTLD-GRN cases, suggesting human-specific neuronal vulnerability. Together, these results broach the hypothesis that PGRN deficiency disrupts the gene regulatory network in microglia and astrocytes and alters intricate glia-neuron interactions to promote neurodegeneration in FLTD-GRN. To test this, we propose to 1) Map the transcriptome and gene regulatory network that define glial pathology and neuronal vulnerability in the frontal cortex and thalamus of FTLD-GRN; 2) characterize the mechanism of cellular resilience in neurons and glia in the visual cortex of FTLD-GRN by mapping their transcriptomes and epigenomes; and 3) delineate the functional consequences of transcriptomic and epigenetic modifications in FTLD-GRN using IPSC-based models. This project will provide critical data that fill the knowledge gaps regarding the trajectories of glial and neuronal pathology, and brain region-specific vulnerability and resilience in FTLD-GRN. Results from this project will further ...