Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY It has become increasingly clear that TDP-43 pathology is associated with a range of neurodegenerative disorders. Great strides have been made to understand the impact of TDP- 43 in ALS and FTD-TDP, two diseases where TDP-43 pathology is a hallmark of disease. Yet, the mechanism(s) by which TDP-43 contributes to neurotoxicity are still not fully understood for any TDP-43 associated disorder. We recently published results from the NYGC ALS Consortium, a large patient profiling study that included whole genome sequencing, deep transcriptome sequencing, and high resolution IHC tissue staining for patients with ALS and FTD. The major finding of this study was that ALS and FTD patients could be grouped into three distinct and robust molecular subtypes, based upon their transcriptome profiles and subsequent IHC validation of key proteins tied to these subtypes. We demonstrated that TDP-43 pathology was most strongly associated with de-silencing of retrotransposons, viral-like elements that are normally silent in most adult tissues. Retrotransposons have been shown to be both neuroinflammatory and neurotoxic in other disease contexts, suggesting a possible contributing mechanism for TDP-43 mediated neurotoxicity. Yet the hypothesis that retrotransposons contribute to TDP-43 mediated cellular toxicity remains untested. This proposal will conclusively test the degree to which retrotransposons contribute to TDP-43 associated toxicity, and the mechanism by which this occurs. Aim 1: How does the cell- and tissue-specific context of TDP-43 pathology affect its impact? We will use multiplexed IHC staining for TDP-43 pathology combined with spatially resolved transcriptomics to conclusively determine which genes and retrotransposons show alterations in cells with TDP-43 pathology in frontal cortex samples from patients with TDP-43 associated common dementias. Aim 2: Do active retrotransposons simply report on TDP-43 pathology or contribute to cellular toxicity? We will test for the ability of TDP-43 dependent retrotransposons to contribute to cellular toxicity in cells with TDP-43 pathology, i.e. cell intrinsic mechanisms. Aim 3: Can TDP-43 dependent retrotransposons contribute to activation of astrocytes and microglia? We will test for the ability of TDP-43 dependent retrotransposons to contribute to activation of adjacent astrocytes and microglia, i.e. cell non-autonomous mechanisms.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
