Autophagy in lurcher mice: Indicted but yet to be acquitted for the death of Purkinje cells

A recent study published in the Journal of Neuroscience by Nishiyama et al., has revisited an autophagy-neurodegeneration model of lurcher (Lc) mice and promoted further discussion regarding the "autophagic cell death" hypothesis.¹ While the study confirmed the previous report by Yue et al., that GluRD2^Lc induces autophagy both in vitro and in vivo, ² it also suggests that GluRD2^Lc-mediated autophagy and cell death occur via pathways outside the nPIST-Beclin 1 pathway.¹ For example, the study makes an interesting observation that GluRD2 ^Lc-induced degeneration is associated with energy crisis and an aberrant AMPK activity. The result provides insight into the downstream events induced by GluRD2^Lc; however, it is not surprising considering that constitutive ion influx caused by the Lc mutation is expected to cause activation of multiple cellular pathways or responses. In conclusion, the authors state that "constitutive ion flux causes cell death with, but not by, autophagy." The conclusion appears consistent with the primary function of autophagy, from an evolutionary point of view, as a survival mechanism. However, careful examination of some results may call into question the conclusion.