Evolutionarily conserved mechanisms in calcium handling may underlie intrinsic sensitivity to dopaminergic neuron death.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Nagarajan et al. Mammalian dopaminergic neurons of the substantia nigra pars compacta (SNc) within the CNS are complex neurons with expansive arborization. Projecting from the SNc to the striatum, the average total axonal length of these neurons in the rat has been estimated to be ϳ467 mm, with each axon supporting upwards of 370,000 synapses (Matsuda et al., 2009). This massive network contributes to our ability to execute movement and degeneration of these neurons has catastrophic effects, as seen in Parkinson's disease (PD). Many hypotheses have been put forth to explain the death of dopaminergic neu-rons in PD, including pathological aggre-gation of ␣-synuclein (a component of Lewy bodies), calcium toxicity, and lyso-somal and mitochondrial dysfunction (Sulzer, 2007). Furthermore, dopamine/␣-synuclein interactions have been suggested as a potential pathogenic mechanism in which dopamine can modify ␣-synuclein to increase its reactivity and aggregative properties. In turn, the reactive aggrega-tion may disrupt the membrane of dopamine-containing vesicles, leading to higher cytoplasmic dopamine levels and further ␣-synuclein modification, or potentially reach cytotoxic levels of dopa-mine, although this hypothesis has just begun to be rigorously tested (Sulzer, 2007; Mosharov et al., 2009). Recent observations in mouse models of PD suggest that interplay between these pathologies might be responsible for dopamingeric cell death of the SNc (Sulzer, 2007). Interestingly , although dopaminergic neurons in both the SNc and the ventral tegmental area (VTA) exhibit Lewy bodies, the neu-rons of the SNc tend to undergo degradation while those of the VTA are relatively spared (Dauer and Przedborski, 2003). Why are VTA neurons spared the de-generative fate of SNc neurons? Calcium toxicity has long been proposed as a mechanism in neuronal cell death, including necrosis and apoptosis. Maintenance of low intracellular calcium levels is essential for cellular function and survival. Interestingly, the calcium binding protein, calbindin, is differentially expressed between VTA and SNc neurons, and single nucleotide polymorphisms in the human calbindin gene, CALB1, have been associated with sporadic PD in a Jap-anese cohort (Mizuta et al., 2008). Calbin-din contains five EF-hand protein motifs that are thought to buffer cytoplasmic calcium levels, thus serving a neuropro-tective function. …