Project Grant R21AG087070

DECIPHERING TDP-43 PROTEINOPATHY: UNVEILING THE CONSEQUENCES ON OLIGODENDROCYTE DYSFUNCTION - TAR-DNA BINDING PROTEIN 43 (TDP-43) IS A NUCLEAR PROTEIN THAT HAS BEEN IMPLICATED IN SEVERAL NEURODEGENERATIVE DISEASES, INCLUDING FRONTOTEMPORAL LOBAR DEGENERATION (FTLD-TDP), AMYOTROPHIC LATERAL SCLEROSIS (ALS), AND LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY (LATE-NC), AMONG OTHER AGE-RELATED DEMENTIAS. THE PRESENCE OF TDP-43 AGGREGATES IN THE CYTOPLASM OF NEURONS AND GLIAL CELLS, PARTICULARLY IN OLIGODENDROCYTES (OLS), IS THE NEUROPATHOLOGICAL HALLMARK OF FTLD-TDP, ALS, AND LATE-NC. SIMILAR TO OTHER MISFOLDED PROTEINS (I.E., A-SYNUCLEIN, B-AMYLOID AND TAU), THE TRANSMISSION OF PATHOGENIC TDP-43 SPECIES BETWEEN CELLS COULD CONTRIBUTE TO DISEASE PROGRESSION IN NEURODEGENERATIVE DISEASES. OUR GROUP HAS RECENTLY SHOWN THAT PATHOLOGICAL TDP-43 DERIVED FROM FTLD-TDP BRAIN EXTRACTS CAN ACT AS PATHOGENIC SEEDS AND INDUCE THE FORMATION OF DE NOVO TDP-43 PATHOLOGY WHEN INJECTED IN THE BRAIN OF TDP-43 TRANSGENIC MICE, AND TO A LESSER EXTENT IN WILD-TYPE MICE (WT). UNDER THIS PARADIGM, TDP-43 PATHOLOGY SPREADS THROUGHOUT THE BRAIN IN A REGIONAL AND TIME-DEPENDENT MANNER. INTERESTINGLY, AS FOUND IN DISEASED HUMAN BRAINS, TDP-43 PATHOLOGY IS PRESENT IN NEURONS AND OLS. DESPITE SEVERAL STUDIES INDICATING THAT TDP-43 PATHOLOGY IN OLS IS A COMMON FEATURE OF VARIOUS NEURODEGENERATIVE DISEASES, INCLUDING AD AND FTLD-TDP, THE CONSEQUENCES OF TDP-43 PATHOLOGY IN OLS REMAINS UNKNOWN. THE PRESENT RESEARCH PROJECT AIMS TO DEVELOP IN VITRO MODELS TO STUDY THE PATHOPHYSIOLOGICAL CONSEQUENCES OF TDP-43 PATHOLOGY IN OLS AND EVALUATE THE ROLE OF OLS IN FACILITATING THE SPREAD OF TDP-43 PATHOGENIC SPECIES BETWEEN GLIAL AND NEURONAL CELLS.