TDP-43 Mediates Degeneration in a NovelDrosophilaModel of Disease Caused by Mutations in VCP/p97

Abstract

Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder caused by mutations in the valosin-containing protein (VCP7) gene. VCP (p97 in mouse, TER94 in Drosophila melanogaster, and CDC48 in Saccharomyces cerevisiae) is a highly conserved AAA ϩ (ATPases associated with multiple cellular activities) ATPase that regulates a wide array of cellular processes. The mechanism of IBMPFD pathogenesis is unknown. To elucidate the pathogenic mechanism, we developed and characterized a Drosophila model of IBMPFD (mutant-VCP-related degeneration). Based on genetic screening of this model, we identified three RNA-binding proteins that dominantly suppressed degeneration; one of these was TBPH, the Drosophila homolog of TAR (trans-activating response region) DNA-binding protein 43 (TDP-43). Here we demonstrate that VCP and TDP-43 interact genetically and that disease-causing mutations in VCP lead to redistribution of TDP-43 to the cytoplasm in vitro and in vivo, replicating the major pathology observed in IBMPFD and other TDP-43 proteinopathies. We also demonstrate that TDP-43 redistribution from the nucleus to the cytoplasm is sufficient to induce cytotoxicity. Furthermore, we determined that a pathogenic mutation in TDP-43 promotes redistribution to the cytoplasm and enhances the genetic interaction with VCP. Together, our results show that degeneration associated with VCP mutations is mediated in part by toxic gain of function of TDP-43 in the cytoplasm. We suggest that these findings are likely relevant to the pathogenic mechanism of a broad array of TDP-43 proteinopathies, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

“…In the brain of these mice, TDP-43 is redistributed from the nucleus to the cytoplasm, in the absence of nuclear inclusions. In a Drosophila model of IBMPFD, a genetic screen has identified TBPH, the fly ortholog of TDP-43, as one of three RNA-binding proteins that dominantly suppress degeneration (Ritson et al 2010). In this model, VCP mutations lead to the redistribution of TDP-43 to the cytoplasm.…”

In Vivo and In Vitro Models to Study Amyotrophic Lateral Sclerosis

“…These findings support the notion that loss of normal TDP-43 function may contribute to the pathogenesis of ALS and FTLD. On the other hand, ubiquitous or tissue-specific overexpression of either dTDP or human TDP-43 also recapitulated key hallmark features of ALS pathology including premature lethality, neuronal loss, neuromuscular junctions architecture defects and locomotor deficits (Elden, et al, 2010;Estes, et al, 2011;Hanson, et al, 2010;Li, et al, 2010;Lu, et al, 2009;Miguel, et al, 2011;Ritson, et al, 2010;Voigt, et al, 2010). Furthermore, TDP-43 expression appears to be independent of ALS/FTLD-linked mutations (Elden, et al, 2010;Estes, et al, 2011;Ritson, et al, 2010;Voigt, et al, 2010).…”

Emerging Roles for hnRNPs in post-transcriptional regulation: what can we learn from flies?

“…In Drosophila, at least three different fly models elucidated the role of TBPH in neuronal and neuromuscular development. Indeed, flies mutants for TBPH closely reproduce most of the phenotypes observed in ALS patients like decreasing viability, affected synaptic transmission, defective locomotion and also age-related progressive neurodegeneration (Ritson et al 2010;Hazelett et al 2012;Li et al 2010;Neumann et al 2006). Recently, it has emerged that TBPH interacts with the Futsch protein, the Drosophila homolog to human MAP1B (Godena et al 2011) (Fig.…”

“…4c) (Tan et al 2012). Another Drosophila hnRNP that seems to be involved in a neuronal physiological process is TBPH, the Drosophila homolog of the human TAR DNA-binding protein (TDP-43 or TARDBP) (Buratti and Baralle 2009;Strong 2010;Buratti and Baralle 2010;Ritson et al 2010). Despite its unequivocal hnRNP structure, TDP-43 was originally described as a DNAbinding protein with a putative role in HIV transcription (Ou et al 1995).…”