Almost all cases of ALS (97%) are associated with pathological forms of TAR-DNA binding protein 43 (TDP-43), which mislocalizes from the nucleus to the cytoplasm and forms inclusions containing misfolded TDP-43. However, it remains unclear how TDP-43 pathology is induced in ALS. Furthermore, no single molecular pathway has been confirmed as causative of disease pathogenesis in ALS. DNA damage has been implicated in the etiology of several neurological disorders, but its role in ALS is still emerging. In this study, I investigated whether DNA damage is involved in the pathogenesis of TDP-43-associated ALS. Upon induction of DNA damage in NSC-34 cells using etoposide, TDP-43 was found to mislocalize into the cytoplasm, where it formed significantly more inclusion-like structures compared to the control cells which were treated with DMSO. These TDP-43 inclusion-like structures displayed immunoreactivity to stress granule marker HuR, suggesting recruitment of TDP-43 into stress granules. Overexpression of TDP-43 with a deleted nuclear localization signal (NLS), which results in the production of TDP-43 mis-localized into the cytoplasm, also induced DNA damage in NSC-34 cells. DNA damage was then examined in a mouse model of TDP-43 in which the pathological cytoplasmic human TDP-43 (hTDP-43) were overexpressed (Walker et al., 2015). Using immunoblot techniques, upregulation of DNA damage was detected in the cortex of these animals compared to age matched control mice. DNA damage was first detected one week after cytoplasmic TDP-43 expression, corresponding to one week before development of symptoms and TDP-43 pathology. Importantly, the extent of DNA damage increased during disease progression, but significantly less damage was present when expression of hTDP-43 was inhibited, during the ‘recovery’ disease phase. These studies therefore demonstrate that DNA damage is closely linked to the formation of TDP-43 pathology in ALS, and they reveal DNA damage as a disease mechanism in TDP-43-associated ALS.
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|Published - 9 Jan 2019
|10th World Congress of Neuroscience (International Brain Research Organization; IBRO2019) - Daegu, Korea, Republic of
Duration: 21 Sept 2019 → 25 Sept 2019