UCSF

The majority of familial FTD stems from mutations in Progranulin (GRN gene, PGRN protein) or hexanucleotide (CCCCGG) repeat expansion in C9orf72 gene. Recent studies highlight the key roles of C9orf72 and PGRN in endo-lysosomal trafficking, with their deficiencies causing abnormal microglial activation in the aging brain. Alongside potential interactions between PGRN and C9orf72 in vesicle trafficking, there are documented instances of concurrent mutations in both C9orf72 and GRN genes linked to earlier disease onset and heightened neurodegeneration in familial cases of FTD-ALS spectrum disease. In my thesis work, I hypothesized that simultaneous deletion of C9orf72 and GRN exacerbates neuroinflammation and neurodegeneration. To test this, I generated aging cohorts of wild type (WT), Grn-/-, C9orf72-/-, and Grn-/-;C9orf72-/- mice. Grn-/-;C9orf72-/- mice exhibited heightened microgliosis and astrogliosis, extending beyond the thalamocortical circuit, and disrupted blood-brain barrier. Brain RNA-seq revealed novel transcriptomics signatures of increases in B-cell receptor signaling in Grn-/-;C9orf72-/- mice. CITE-seq and flow cytometry revealed age-dependent clonal expansions of age-associated B cells and activated B cells. PhIP-seq and protein arrays demonstrated that clonally expanded B cells produced autoantibodies that target many neural antigens, including axon guidance protein ROBO3. Together, these results support that concurrent loss-of-function in both C9orf72 and Grn genes intensify neuroinflammation and peripheral immune system defects, thereby synergistically promoting neurodegeneration.