BCL‐2 counteracts Doppel‐induced apoptosis of prion‐protein‐deficient Purkinje cells in the Ngsk Prnp^0/0 mouse

Abstract

The pro-apoptotic factor BAX has recently been shown to contribute to Purkinje cell (PC) apoptosis induced by the neurotoxic prion-like protein Doppel (Dpl) in the prion-protein-deficient Ngsk Prnp(0/0) (NP(0/0)) mouse. In view of cellular prion protein (PrP(c)) ability to counteract Dpl neurotoxicity and favor neuronal survival like BCL-2, we investigated the effects of the anti-apoptotic factor BCL-2 on Dpl neurotoxicity by studying the progression of PC death in aging NP(0/0)-Hu-bcl-2 double mutant mice overexpressing human BCL-2 (Hu-bcl-2). Quantitative analysis showed that significantly more PCs survived in NP(0/0)-Hu-bcl-2 double mutants compared with the NP(0/0) mutants. However, number of PCs remained inferior to wild-type levels and to the increased number of PCs observed in Hu-bcl-2 mutants. In the NP(0/0) mutants, Dpl-induced PC death occurred preferentially in the aldolase C-negative parasagittal compartments of the cerebellar cortex. Activation of glial cells exclusively in these compartments, which was abolished by the expression of Hu-bcl-2 in the double mutants, suggested that chronic inflammation is an indirect consequence of Dpl-induced PC death. This partial rescue of NP(0/0) PCs by Hu-bcl-2 expression was similar to that observed in NP(0/0):Bax(-/-) double mutants with bax deletion. Taken together, these data strongly support the involvement of BCL-2 family-dependent apoptotic pathways in Dpl neurotoxicity. The capacity of BCL-2 to compensate PrP(c) deficiency by rescuing PCs from Dpl-induced death suggests that the BCL-2-like property of PrP(c) may impair Dpl-like neurotoxic pathways in wild-type neurons.

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…Consequently, four studies have recently reported that cell death in N-terminal truncated overpressing mice and in the Nagasaki line is regulated in a Bcl-2/BAX manner (Heitz et al, 2008;Heitz et al, 2007;Li et al, 2007a;Nicolas et al, 2007) (see Table 1). Surprisingly, contradictory results have been obtained in the latter strain, regarding the contribution of BAX depletion to ataxic syndrome rescue (Dong et al, 2007;Heitz et al, 2007).…”

PRND (Prion Protein 2 (Dublet))

“…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).…”

Doppel induces autophagic stress in prion protein-deficient Purkinje cells

“…While investigating the involvement of the Bcl-2 family members in Dpl-mediated apoptosis of NP 0/0 Purkinje cells, these neurons were partially rescued in either Bax-deficient (NP 0/0 :Bax -/-) or bcl-2 overexpressing (NP 0/0 -Hu-bcl-2) double mutant mice, implying that Dpl triggers both Bax-dependent apoptosis and Bax-independent neurotoxic mechanisms in the NP 0/0 Purkinje cells. 1,6,7 Given that the scrapie-responsive gene Scrg1 is potentially associated with autophagy and is abnormally expressed in NP 0/0 Purkinje cells and prion-diseased neurons, 8 and that reactive oxygen species (ROS) can activate both apoptosis 9 and autophagy, 10,11 we examined the possible role of autophagy in Dpl-induced neuronal death. In NP 0/0 mice, robust autophagy was observed in Purkinje cells well before significant neuronal loss.…”

“…This effect could convert an initial autophagic defensive reaction into a neurodegenerative mechanism. 1,6 Increased or continued requirements for autophagy coupled with an impairment in the late phases of autophagic flux (i.e., completion of the lysosomal degradation process) may lead to autophagic stress. 15 The leakage of hydrolases induced by membrane destabilization of autolysosomes and lysosomes could trigger apoptotic cascades.…”

“…Indeed, these neurons exhibit different resistance levels to Dpl toxicity depending on their antero-posterior and parasagittal position in the cerebellar cortex. 1,6 Interestingly, in another mouse mutant model, GluRδ2 Lurcher, autophagy has also been shown to precede apoptosis in Purkinje cells. In GluRδ2 Lc/+ Purkinje cells, the higher incidence of auto phagosomes in axons compared with cell bodies and dendrites provides clear evidence of an axonal origin of autophagosomes.…”