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Xenotransplantation of genetically engineered iPSC-derived microglia and neurons to decipher the cell-type specific interplay of Progranulin and TMEM106B in neuroinflammation and neurodegeneration.

Frontotemporal lobar degeneration (FTLD) is an early-onset form of dementia representing 10-20% of all dementia cases. It is characterized by the loss of neurons in the frontal and temporal lobes resulting in a dramatic impact on core human qualities including personality, insight and verbal communication. Aggregates of the TAR DNA-binding protein 43 (TDP-43) are the hallmark of the most common pathological subtype of FTLD (FTLD-TDP). Importantly, over the past decade, the field of neurodegeneration has shifted from a proteinopathy-centric view towards the concept of a multicellular hypothesis underlying both initiation and perpetuation of disease. Genetic studies have helped significantly in deciphering the cellular substrate of neurodegeneration. In relation to FTLD, the Rademakers lab identified loss-of-function mutations in progranulin (GRN) as one of the major genetic causes of FTLD. They also described TMEM106B genetic variants as the first genetic risk factor for FTLD-TDP and found that TMEM106B protective variants can dramatically reduce the disease penetrance of GRN mutations. GRN and TMEM106B are enriched in separate cellular compartments (microglia versus neurons, respectively), depicting a scenario where different genetic factors interact from multiple cellular compartments. We hypothesise that the genetic risk shapes cellular responses and phenotypes promoting particular disease states in microglia which modify the vulnerability of neurons to degeneration. We propose to investigate this concept in the context of FTLD and age-related TDP-43 neuropathology using the established disease genes GRN and TMEM106B in microglia and neurons, respectively. However, the study of genotype-phenotype interactions in neurodegeneration is not trivial, as there is a limited homology between human and mouse in terms of expression of disease associated genes. To overcome this limitation, the Mancuso lab has developed a model of human iPSC-derived brain cells xenotransplantation to study human relevant genetic traits in a diseased mouse brain environment. In a joined effort from the Rademakers and Mancuso labs, we here propose to investigate the impact of GRN and TMEM106B genetic variants by iPSC microglia and neurons derivation, and xenotransplantation, in FTLD (Grn-/-) and wild type mice. We plan to 1) generate isogenic series of iPSC lines containing GRN and TMEM106B mutations; 2) determine the impact of GRN deficiency in human microglia and determine whether this deficiency is sufficient to induce neuropathology in the mouse brain; and 3) determine if changes in TMEM106B expression in human neurons lead to susceptibility or resilience against degeneration, in vivo. Our studies will provide critical knowledge on the diverse cellular processes underlying FTLD and we expect the novel insights gained from this research to be invaluable for the development of novel therapeutic strategies for FTLD patients and related disorders.
Date:1 Jan 2022 →  Today
Disciplines:Single-cell data analysis, Inflammation, Cell death , Neurological and neuromuscular diseases