Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS

Amyotrophic lateral sclerosis (als) and frontotemporal lobar degeneration (ftld) are two incurable neurodegenerative disorders that exist on a symptomological spectrum and share both genetic underpinnings and pathophysiological hallmarks. functional abnormality of tar dna-binding protein 43 (tdp-43),an aggregation-prone rna and dna binding protein,is observed in the vast majority of both familial and sporadic als cases and in ~40% of ftld cases,but the cascade of events leading to cell death are not understood. we have expressed human tdp-43 (htdp-43) in drosophila neurons and glia,a model that recapitulates many of the characteristics of tdp-43-linked human disease including protein aggregation pathology,locomotor impairment,and premature death. we report that such expression of htdp-43 impairs small interfering rna (sirna) silencing,which is the major post-transcriptional mechanism of retrotransposable element (rte) control in somatic tissue. this is accompanied by de-repression of a panel of both line and ltr families of rtes,with somewhat different elements being active in response to htdp-43 expression in glia versus neurons. htdp-43 expression in glia causes an early and severe loss of control of a specific rte,the endogenous retrovirus (erv) gypsy. we demonstrate that gypsy causes the degenerative phenotypes in these flies because we are able to rescue the toxicity of glial htdp-43 either by genetically blocking expression of this rte or by pharmacologically inhibiting rte reverse transcriptase activity. moreover,we provide evidence that activation of dna damage-mediated programmed cell death underlies both neuronal and glial htdp-43 toxicity,consistent with rte-mediated effects in both cell types. our findings suggest a novel mechanism in which rte activity contributes to neurodegeneration in tdp-43-mediated diseases such as als and ftld. © 2017 krug et al.