Investigating Dysfunction of Neuroimmune-Related Processes in Models of ALS/FTD TDP-43

ABSTRACT
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with
overlapping genetic and pathological features. While neuronal degeneration predicts the clinical and pathological
manifestations of these disorders, non-neuronal cells significantly contribute to disease pathogenesis. Indeed,
alterations in immune response and dysregulation of microglia are early features of ALS and FTD, and are believed to
contribute to disease progression. A prominent, pathological feature of ALS, FTD and related neurodegenerative
diseases is TAR DNA binding protein 43 (TDP-43) dysfunction. TDP-43 is an RNA/DNA-binding protein with many
roles in RNA and DNA processing, yet the role of TDP-43 in these neurodegenerative diseases remains poorly defined.
We have been investigating the link between traumatic brain injury (TBI) and neurodegeneration, as TBI is a known
risk-factor for developing neurological disorders with TDP-43 pathology. Using a knock-in mouse model of mutant
TDP-43 (i.e., ALS/FTD-TDP mice), we conducted neurological and omics analyses in ALS/FTD-TDP versus WT
mice following a mild, concussive TBI. We found that ALS/FTD-TDP mice are more susceptible to neurological
deficits following TBI compared to their WT counterparts, a phenotype that was accompanied by changes in innate
immune pathways involved in nucleic acid sensing in ALS/FTD-TDP mice. Microglia are key modulators of innate
immunity in the CNS, and are critical for recovery after injury. Therefore, Aim 1 in this proposal will probe innate
immune pathways and characterize CNS cell types, including microglia subtypes, within ALS/FTD-TDP mice both at
baseline and after TBI. To investigate the mechanistic impact of TDP-43 dysfunction on the properties of microglia,
we will also employ a human induced pluripotent stem cell (iPSC) derived microglia (iMG) model in Aim 2.
Complementary to our ALS/FTD-TDP mouse model, iMGs will allow us to determine the effects of TDP-43 mutation
or TDP-43 knock-down on microglial function. We will further utilize this iMG model through xenotransplantation of
iMGs into the mouse brain, allowing us to elucidate the impact of TDP-43 mutation specifically in microglia in vivo.
The outcomes of this proposal have the potential to uncover mechanisms by which TDP-43 mis-expression alters the
innate immune landscape in the CNS, including under conditions of CNS insult.

Grant Number: 1R21NS139100-01A1
NIH Institute/Center: NIH
Principal Investigator: Daryl Bosco