Onditions (Wilson and Callaway, 2000; Chan et al., 2007). Second, DA neurons of the substantia nigra show an elaborate axonal network (Matsuda et al., 2009), supporting orders of magnitude far more synapses compared to a cortical pyramidal neuron (Arbuthnott and Wickens, 2007). Consequently, the Fluorometholone Autophagy mitochondrial density in their somatic and dendritic regions is quite low when compared with other neuronal sorts (Liang et al., 2007). Taken collectively, these qualities are believed to contribute to an intrinsic state of elevated metabolic stress, exactly where enhanced load of intracellular Ca2+ is met by a depleted mitochondrial network. Extra genetic elements could enhance the rate at which mitochondrial Ca2+ homeostasis is compromised in these currently vulnerable neurons. At the least 13 gene loci and 9 genes happen to be linked to each autosomal dominant and recessive types of PD (Lesage and Brice, 2009). Mutations in three proteins encoded by these genes, namely, parkin (PARK2), DJ-1 (PARK7), and PINK1 (PARK6 ), are connected with recessive early onset types of PD, whereas mutations in -synuclein (PARK1) and LRRK2 (PARK8 ) are accountable for dominant types of familial PD. Mitochondrial dysfunction has been described for mutants of all these genes (Lesage and Brice, 2009). Current papers have started to discover in more detail the possibility of Ca2+ handling by the PD-related proteins. DJ-1 is actually a multitask protein that, as well as its key function as an antioxidant (Taira et al., 2004), is also involved in sustaining cytosolic basal Ca2+ concentration values to permit depolarization-induced Ca2+ release from the sarcoplasmic reticulum in muscle cells (Shtifman et al., 2011). Furthermore, DJ-1 was shown to shield DA neurons from Ca2+ -induced mitochondrial uncoupling and ROS production during physiological pacemaking (Guzman et al., 2010). With regards to -synuclein, it has been described that it can modulate Ca2+ influx in the extracellular milieu by enhancing the plasma membrane ion permeability (Danzer et al., 2007) either by way of their direct insertion in to the plasma membrane and the formation of a pore (Lashuel et al., 2002) or via the modulation of plasma membrane Ca2+ permeability (Furukawa et al., 2006). The actual mechanisms via which -synuclein aggregation and Ca2+ dysfunction influence each other will not be clear, having said that, a functional interplay is unambiguous: Enhanced intracellular Ca2+ promotes -synuclein aggregation, which in turn could promote intracellular Ca2+ increase (Nath et al., 2011). A recent study suggests that employing its C-terminal domain, synuclein Maleimide In Vivo controls mitochondrial calcium homeostasis by enhancing ER itochondria interactions (Cali et al., 2012). As theseFrontiers in Genetics | Genetics of AgingOctober 2012 | Volume 3 | Post 200 |Nikoletopoulou and TavernarakisAging and Ca2+ homeostasisresults had been obtained in vitro working with non-neuronal cell lines, their relevance to DA neuron physiology and pathology remains to be examined. As to PINK1, its direct function in regulating cellular, and most specifically mitochondrial Ca2+ fluxes, has been not too long ago proposed starting together with the observation that the co-expression of mutant PINK1 within a cellular model of PD-expressing mutated synuclein exacerbated the observed mitochondrial defects, that’s, enhanced mitochondrial size with loss of cristae and reduced ATP levels (Marongiu et al., 2009). The proposed mechanisms of PINK1 action was based on a deregulation of mitochondrial Ca2+ influx.