Onditions (Wilson and Callaway, 2000; Chan et al., 2007). Second, DA neurons with the substantia nigra display an elaborate axonal network (Matsuda et al., 2009), supporting orders of magnitude extra synapses when compared with a cortical pyramidal neuron (Arbuthnott and Wickens, 2007). Consequently, the mitochondrial density in their somatic and dendritic regions is very low in comparison with other neuronal varieties (Liang et al., 2007). Taken with each other, these traits are believed to contribute to an intrinsic state of elevated metabolic anxiety, where increased load of intracellular Ca2+ is met by a depleted mitochondrial network. Added genetic things could increase the price at which mitochondrial Ca2+ homeostasis is compromised in these already vulnerable neurons. At the least 13 gene loci and 9 genes have been linked to both 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 related with recessive early onset forms 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). Recent papers have began to discover in more detail the possibility of Ca2+ handling by the PD-related proteins. DJ-1 is usually a multitask protein that, in addition to its major function as an antioxidant (Taira et al., 2004), can also be involved in keeping cytosolic basal Ca2+ concentration values to permit depolarization-induced Ca2+ release from the sarcoplasmic reticulum in muscle cells (Shtifman et al., 2011). In addition, DJ-1 was shown to shield DA neurons from Ca2+ -induced mitochondrial uncoupling and ROS production through physiological pacemaking (Guzman et al., 2010). Regarding -synuclein, it has been described that it might modulate Ca2+ influx in the extracellular milieu by Acidogenesis pathway Inhibitors products enhancing the plasma membrane ion permeability (Danzer et al., 2007) either via their direct insertion into the plasma membrane and also the formation of a pore (Lashuel et al., 2002) or by way of the modulation of plasma membrane Ca2+ permeability (Furukawa et al., 2006). The actual mechanisms by means of which -synuclein aggregation and Ca2+ dysfunction Nicarbazin Formula influence one another are certainly not clear, on the other hand, a functional interplay is unambiguous: Improved intracellular Ca2+ promotes -synuclein aggregation, which in turn could promote intracellular Ca2+ boost (Nath et al., 2011). A recent study suggests that employing its C-terminal domain, synuclein controls mitochondrial calcium homeostasis by enhancing ER itochondria interactions (Cali et al., 2012). As theseFrontiers in Genetics | Genetics of AgingOctober 2012 | Volume 3 | Report 200 |Nikoletopoulou and TavernarakisAging and Ca2+ homeostasisresults have been obtained in vitro working with non-neuronal cell lines, their relevance to DA neuron physiology and pathology remains to become examined. As to PINK1, its direct role in regulating cellular, and most particularly mitochondrial Ca2+ fluxes, has been recently proposed beginning together with the observation that the co-expression of mutant PINK1 inside a cellular model of PD-expressing mutated synuclein exacerbated the observed mitochondrial defects, that is, enhanced mitochondrial size with loss of cristae and decreased ATP levels (Marongiu et al., 2009). The proposed mechanisms of PINK1 action was determined by a deregulation of mitochondrial Ca2+ influx.
