20p13

DOPPEL,DPL,PrPLP,dJ1068H6.4

Ectopic Doppel expression associated with Purkinje cell neurodegeneration in transgenic mouse models.

Beside its role in male reproductive system, Doppel has attracted interest for its neurotoxic properties when ectopically expressed in the brain of Tg mice knock-out for the prion protein gene (Prnp^0/0 mice). In these mice, denoted as Ngsk PrP^-/-, the Doppel-encoding exon was expressed as chimeric mRNA due to the intergenic splicing taking place between Prnp and Prnd. As a result, Prnd became abnormally regulated under the control of Prnp promoter and ectopically expressed in the brain and, in particular, in neurons and glial cells (Li et al., 2000). Similar non-physiological Doppel expression was reported in other Tg mouse lines knock-out for Prnp such as Rcm0 and Zrch mice (Moore et al., 2001; Rossi et al., 2001). Doppel expression in the brain is neurotoxic and causes Purkinje cell degeneration in these mouse models. Doppel neurotoxicity is antagonized by the PrP^C N-terminal domain (Atarashi et al., 2003; Yamaguchi et al., 2004). The neuroprotective PrP^C role against ectopic Doppel expression has been reported also in human neuronal SH-SY5Y cells (Li et al., 2009) confirming the dominant-negative effects of the PrP^C N-terminal region (Yoshikawa et al., 2008). The molecular mechanisms leading to Doppel-induced neurodegeneration in Purkinje and granular cells are still controversial. An earlier study has reported that the chimeric form of Doppel fused to a Fc domain binds specifically granule cells and causes neurodegeneration, raising the possibility that these specific cells expressed a still unidentified protein that mediates the Doppel-induced neurotoxicity (Legname et al., 2002). Oxidative stress may play a role in Doppel-induced neuronal death since NOS activity is induced by Doppel in vitro and in vivo (Cui et al., 2003; Wong et al., 2001). Two independent groups have reported that BAX contributes to Doppel-induced apoptosis (Didonna et al., 2012; Heitz et al., 2007) and that BCL-2 antagonizes Doppel neurotoxicity (Heitz et al., 2008). Another work has observed that ectopic Doppel expression in the brain elicits neurodegeneration through the binding of two metalloproteinase namely the alpha-1-inhibitor-3 (α1I3) and the alpha-2-macroglobin (α2M) (Benvegnu et al., 2009).

Abnormal Doppel expression levels in human astrocytomas and other non-glial brain tumor specimens

Doppel is aberrantly expressed in astrocytic tumors where it displays cytoplasmic, nuclear and lysosomal localization and molecular properties (i.e. altered glycosilation pattern) different from Doppel as normally expressed in testis (Azzalin et al., 2006; Azzalin et al., 2008; Comincini et al., 2006; Comincini et al., 2004; Comincini et al., 2007; Rognoni et al., 2010; Sbalchiero et al., 2008).