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  • In neurodegenerative disorders neurons are excited by enormo

    2020-03-26

    In neurodegenerative disorders neurons are excited by enormous ionic flow which induces mitochondrial dysfunction and apoptosis. Glutamate as the main excitatory neurotransmitter, is released excessively in these diseases. Glutamate acts through N-methyl-d-aspartate (NMDA) receptor and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic 3902 mg (AMPA) receptors (Hara and Snyder, 2007). In AD, amyloid beta (Aβ) increases excitatory by influencing NMDA receptors indirectly (Deng et al., 2014). Moreover, in AD glutamate reuptake from the synaptic cleft is decreased because of Aβ (Scimemi et al., 2013). Previous studies showed that agonists for NMDA receptor increases neurodegeneration in the striatum like HD (Coyle and Schwarcz, 1976). NMDA receptors are more active in various HD mouse models (Shehadeh et al., 2006). Accumulation of glutamate in the synaptic cleft and over activity of NMDA receptors was reported in PD (Zhang et al., 2016). NMDA activation by glutamate not only excites postsynaptic neurons but also increase Ca influx into the cell (Zipfel et al., 2000). Mitochondria buffer cytoplasmic Ca primarily by using uniporters which are opened in the high concentration of Ca (Rizzuto et al., 2000). Influx of the Ca into the mitochondrial matrix depends on the electrochemical gradient. Mitochondrial membrane potential (ΔΨ) is generated by respiratory chain during oxidative phosphorylation (Sparagna et al., 1995). In neuronal cells preventing Ca uptake by mitochondria protects them against injuries and degeneration (Stout et al., 1998). Mitochondrial Ca overload increases ROS production, decrease or complete loss of ΔΨ, opening of the PTP, disrupts mitochondrial activity and finally ATP depletion (Giorgi et al., 2012). Some studies showed crosstalk between Ca hemostasis and neurodegeneration. For example, in AD model Aβ inserts into the plasma membrane and increase Ca influx into the cytoplasm by acting as ion channel (Demuro et al., 2005). Moreover, Aβ oligomer causes mitochondrial Ca overload. Excessive Ca in mitochondria elevates ROS generation, inhibits ATP production and triggers apoptosis by releasing cytochrome c (Brustovetsky et al., 2003). Like AD, in PD models accumulation of α-synuclein increases Ca influx into the neuron (Furukawa et al., 2006). PTEN-induced putative kinase 1 (PINK1) is a mitochondrial protein which shows PD etiology in the mutant form. Some evidences show that in the PINK1 deficient mouse, mitochondria are sensitive to Ca in dopaminergic neurons (Akundi et al., 2011). HD is characterized by the neurodegeneration in striatum. Abnormal expansion of poly glutamine (Poly Q) in Huntingtin protein (Htt) is the main reason of HD. Mutant form of the huntingtin (mHtt) makes neurons vulnerable to Ca overloading which leads to apoptosis and degeneration of neurons (Choo et al., 2004). Mitochondria play crucial role in the cytoplasmic Ca buffering and overloading of the mitochondria with Ca not only disrupt mitochondrial function but also triggers other signaling pathways which leads to neurodegeneration. Mitochondrion has distinct DNA (mtDNA) which encodes some proteins of respiratory chain and specific rRNA and tRNA for mitochondria. Human mtDNA is double strands circular molecule with approximately 16.6 base pairs which encodes 2 rRNA, 22 tRNA and 13 polypeptides of the respiratory chain (Eichner and Giguère, 2011, Legros et al., 2004). Complex I (NADH CoQ dehydrogenase) contains 45 subunits which seven of them are encoded by mtDNA (Davis and Williams, 2012). 1-methyl 4-phenyl 1,2,3,6 tetrahydropyridine (MPTP), or more specifically its active metabolite 1-methyl 4-phenylpyridinium (MPP+) inhibits complex I in dopaminergic neurons which leads to degeneration of dopaminergic neurons (Langston and Ballard, 1983, Jodeiri Farshbaf et al., 2016a). Previous studies showed PD and HD patients have inactive complex I in their platelets (Haas et al., 1995, Silva et al., 2013). In addition to neurotoxins such as MPP+, deletion in mtDNA is provided in the dopaminergic neurons of the PD patients (Kraytsberg et al., 2006).