Abstract
Calcium (Ca2+) is an almost universal second messenger that regulates important activities of all eukaryotic cells. It is of critical importance to neurons, which have developed extensive and intricate pathways to couple the Ca2+ signal to their biochemical machinery. In particular, Ca2+ participates in the transmission of the depolarizing signal and contributes to synaptic activity. During aging and in neurodegenerative disease processes, the ability of neurons to maintain an adequate energy level can be compromised, thus impacting on Ca2+ homeostasis. In Parkinson’s disease (PD), many signs of neurodegeneration result from compromised mitochondrial function attributable to specific effects of toxins on the mitochondrial respiratory chain and/or to genetic mutations. Despite these effects being present in almost all cell types, a distinguishing feature of PD is the extreme selectivity of cell loss, which is restricted to the dopaminergic neurons in the ventral portion of the substantia nigra pars compacta. Many hypotheses have been proposed to explain such selectivity, but only recently it has been convincingly shown that the innate autonomous activity of these neurons, which is sustained by their specific Cav1.3 L-type channel pore-forming subunit, is responsible for the generation of basal metabolic stress that, under physiological conditions, is compensated by mitochondrial buffering. However, when mitochondria function becomes even partially compromised (because of aging, exposure to environmental factors or genetic mutations), the metabolic stress overwhelms the protective mechanisms, and the process of neurodegeneration is engaged. The characteristics of Ca2+ handling in neurons of the substantia nigra pars compacta and the possible involvement of PD-related proteins in the control of Ca2+ homeostasis will be discussed in this review.
Similar content being viewed by others
References
Abramov AY, Gegg M, Grunewald A, Wood NW, Klein C, Schapira AH (2011) Bioenergetic consequences of PINK1 mutations in Parkinson disease. PLoS One 6:e25622
Adamczyk A, Strosznajder JB (2006) Alpha-synuclein potentiates Ca2+ influx through voltage-dependent Ca2+ channels. Neuroreport 17:1883–1886
Akundi RS, Huang Z, Eason J, Pandya JD, Zhi L, Cass WA, Sullivan PG, Bueler H (2011) Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in pink1-deficient mice. PLoS One 6:e16038
Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, Thomas B, Ko HS, Sasaki M, Ischiropoulos H, Przedborski S, Dawson TM, Dawson VL (2007) DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci U S A 104:14807–14812
Ashrafi G, Schwarz TL (2013) The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ 20:31–42
Auluck PK, Caraveo G, Lindquist S (2010) Alpha-synuclein: membrane interactions and toxicity in Parkinson's disease. Annu Rev Cell Dev Biol 26:211–233
Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, Jacob Filho W, Lent R, Herculano-Houzel S (2009) Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol 513:532–541
Baldi I, Cantagrel A, Lebailly P, Tison F, Dubroca B, Chrysostome V, Dartigues JF, Brochard P (2003) Association between Parkinson's disease and exposure to pesticides in southwestern France. Neuroepidemiology 22:305–310
Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341–345
Bazzazi H, Ben Johny M, Adams PJ, Soong TW, Yue DT (2013) Continuously tunable Ca(2+) regulation of RNA-edited CaV1.3 channels. Cell Rep 5:367–377
Bean BP (2007) The action potential in mammalian central neurons. Nat Rev Neurosci 8:451–465
Beaulieu JM, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63:182–217
Becker C, Jick SS, Meier CR (2008) Use of antihypertensives and the risk of Parkinson disease. Neurology 70:1438–1444
Bendor JT, Logan TP, Edwards RH (2013) The function of alpha-synuclein. Neuron 79:1044–1066
Berridge MJ (1998) Neuronal calcium signaling. Neuron 21:13–26
Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3:1301–1306
Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of aging and cognitive decline. Nature 464:529–535
Bolam JP, Hanley JJ, Booth PA, Bevan MD (2000) Synaptic organisation of the basal ganglia. J Anat 196:527–542
Bonifati V, Rizzu P, Baren MJ van, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, Dongen JW van, Vanacore N, Swieten JC van, Brice A, Meco G, Duijn CM van, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism. Science 299:256–259
Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, Marchi S, Patergnani S, Rimessi A, Suski JM, Wojtala A, Wieckowski MR, Kroemer G, Galluzzi L, Pinton P (2013) Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674–683
Brini M, Calì T, Ottolini D, Carafoli E (2014) Neuronal calcium signaling: function and dysfunction. Cell Mol Life Sci. doi. doi:10.1007/s00018-013-1550-7
Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:1663–1667
Buttner S, Faes L, Reichelt WN, Broeskamp F, Habernig L, Benke S, Kourtis N, Ruli D, Carmona-Gutierrez D, Eisenberg T, D'Hooge P, Ghillebert R, Franssens V, Harger A, Pieber TR, Freudenberger P, Kroemer G, Sigrist SJ, Winderickx J, Callewaert G, Tavernarakis N, Madeo F (2013) The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca(2+) levels to alpha-synuclein toxicity in Parkinson's disease models. Cell Death Differ 20:465–477
Calì T, Ottolini D, Brini M (2011) Mitochondria, calcium, and endoplasmic reticulum stress in Parkinson's disease. Biofactors 37:228–240
Calì T, Ottolini D, Brini M (2012a) Mitochondrial Ca2+ and neurodegeneration. Cell Calcium 52:73–85
Calì T, Ottolini D, Negro A, Brini M (2012b) Alpha-synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions. J Biol Chem 287:17914–17929
Calì T, Ottolini D, Brini M (2013a) Calcium and endoplasmic reticulum-mitochondria tethering in neurodegeneration. DNA Cell Biol 32:140–146
Calì T, Ottolini D, Negro A, Brini M (2013b) Enhanced parkin levels favour ER-mitochondria crosstalk and guarantee Ca2+ transfer to sustain cell bioenergetics. BBA - Mol Basis Dis 495–508
Cardenas C, Miller RA, Smith I, Bui T, Molgo J, Muller M, Vais H, Cheung KH, Yang J, Parker I, Thompson CB, Birnbaum MJ, Hallows KR, Foskett JK (2010) Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142:270–283
Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Surmeier DJ (2007) “Rejuvenation” protects neurons in mouse models of Parkinson's disease. Nature 447:1081–1086
Cherra SJ 3rd, Steer E, Gusdon AM, Kiselyov K, Chu CT (2013) Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol 182:474–484
Cisek P, Kalaska JF (2010) Neural mechanisms for interacting with a world full of action choices. Annu Rev Neurosci 33:269–298
Cohen G (1984) Oxy-radical toxicity in catecholamine neurons. Neurotoxicology 5:77–82
Collier TJ, Lipton J, Daley BF, Palfi S, Chu Y, Sortwell C, Bakay RA, Sladek JR Jr, Kordower JH (2007) Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: diminished compensatory mechanisms as a prelude to Parkinsonism. Neurobiol Dis 26:56–65
Collier TJ, Kanaan NM, Kordower JH (2011) Aging as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates. Nat Rev Neurosci 12:359–366
Connors BW, Gutnick MJ (1990) Intrinsic firing patterns of diverse neocortical neurons. Trends Neurosci 13:99–104
Cookson MR (2012) Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways. Cold Spring Harb Perspect Med 2:a009415
Damier P, Hirsch EC, Agid Y, Graybiel AM (1999) The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28 K) immunohistochemistry. Brain 122:1421–1436
Day M, Wang Z, Ding J, An X, Ingham CA, Shering AF, Wokosin D, Ilijic E, Sun Z, Sampson AR, Mugnaini E, Deutch AY, Sesack SR, Arbuthnott GW, Surmeier DJ (2006) Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nat Neurosci 9:251–259
De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336–340
de Vries RL, Przedborski S (2013) Mitophagy and Parkinson's disease: be eaten to stay healthy. Mol Cell Neurosci 55:37–43
DeLong MR (1990) Primate models of movement disorders of basal ganglia origin. Trends Neurosci 13:281–285
Dick FD, De Palma G, Ahmadi A, Scott NW, Prescott GJ, Bennett J, Semple S, Dick S, Counsell C, Mozzoni P, Haites N, Wettinger SB, Mutti A, Otelea M, Seaton A, Soderkvist P, Felice A (2007) Environmental risk factors for Parkinson's disease and Parkinsonism: the Geoparkinson study. Occup Environ Med 64:666–672
Diogenes MJ, Dias RB, Rombo DM, Vicente Miranda H, Maiolino F, Guerreiro P, Nasstrom T, Franquelim HG, Oliveira LM, Castanho MA, Lannfelt L, Bergstrom J, Ingelsson M, Quintas A, Sebastiao AM, Lopes LV, Outeiro TF (2012) Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J Neurosci 32:11750–11762
Doig NM, Moss J, Bolam JP (2010) Cortical and thalamic innervation of direct and indirect pathway medium-sized spiny neurons in mouse striatum. J Neurosci 30:14610–14618
Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, Marshall FJ, Ravina BM, Schifitto G, Siderowf A, Tanner CM (2007) Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68:384–386
Dryanovski DI, Guzman JN, Xie Z, Galteri DJ, Volpicelli-Daley LA, Lee VM, Miller RJ, Schumacker PT, Surmeier DJ (2013) Calcium entry and alpha-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons. J Neurosci 33:10154–10164
Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K (2010) Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival.J Neurosci 30:6838-6851
Erisir A, Lau D, Rudy B, Leonard CS (1999) Function of specific K(+) channels in sustained high-frequency firing of fast-spiking neocortical interneurons. J Neurophysiol 82:2476–2489
Exner N, Lutz AK, Haass C, Winklhofer KF (2012) Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences. EMBO J 31:3038–3062
Fahn S (2008) The history of dopamine and levodopa in the treatment of Parkinson's disease. Mov Disord 23(Suppl 3):S497–508
Firestone JA, Smith-Weller T, Franklin G, Swanson P, Longstreth WT Jr, Checkoway H (2005) Pesticides and risk of Parkinson disease: a population-based case-control study. Arch Neurol 62:91–95
Follett J, Darlow B, Wong MB, Goodwin J, Pountney DL (2013) Potassium depolarization and raised calcium induces alpha-synuclein aggregates. Neurotox Res 23:378–392
Forti L, Cesana E, Mapelli J, D'Angelo E (2006) Ionic mechanisms of autorhythmic firing in rat cerebellar Golgi cells. J Physiol (Lond) 574:711–729
Fujimura K, Matsuda Y (1989) Autogenous oscillatory potentials in neurons of the guinea pig substantia nigra pars compacta in vitro. Neurosci Lett 104:53–57
Furukawa K, Matsuzaki-Kobayashi M, Hasegawa T, Kikuchi A, Sugeno N, Itoyama Y, Wang Y, Yao PJ, Bushlin I, Takeda A (2006) Plasma membrane ion permeability induced by mutant alpha-synuclein contributes to the degeneration of neural cells. J Neurochem 97:1071–1077
Galione A (2011) NAADP receptors. Cold Spring Harb Perspect Biol 3:a004036
Gandhi S, Muqit MM, Stanyer L, Healy DG, Abou-Sleiman PM, Hargreaves I, Heales S, Ganguly M, Parsons L, Lees AJ, Latchman DS, Holton JL, Wood NW, Revesz T (2006) PINK1 protein in normal human brain and Parkinson's disease. Brain 129:1720–1731
Gandhi S, Wood-Kaczmar A, Yao Z, Plun-Favreau H, Deas E, Klupsch K, Downward J, Latchman DS, Tabrizi SJ, Wood NW, Duchen MR, Abramov AY (2009) PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 33:627–638
Gandhi S, Vaarmann A, Yao Z, Duchen MR, Wood NW, Abramov AY (2012) Dopamine induced neurodegeneration in a PINK1 model of Parkinson's disease. PLoS One 7:e37564
Garcia Ruiz PJ, Catalan MJ, Fernandez Carril JM (2011) Initial motor symptoms of Parkinson disease. Neurologist 17:S18–S20
Gautier CA, Giaime E, Caballero E, Nunez L, Song Z, Chan D, Villalobos C, Shen J (2012) Regulation of mitochondrial permeability transition pore by PINK1. Mol Neurodegener 7:22
Gerfen CR, Surmeier DJ (2011) Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 34:441–466
Gerfen CR, Wilson CJ (1996) The basal ganglia. In: Swanson LW, Bjorklund A, Hökfelt T (eds) Handbook of chemical neuroanatomy, vol 12. Elsevier, Amsterdam, pp 371-468
Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ Jr, Sibley DR (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429–1432
Gerfen CR, Miyachi S, Paletzki R, Brown P (2002) D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase. J Neurosci 22:5042–5054
German DC, Manaye KF, Sonsalla PK, Brooks BA (1992) Midbrain dopaminergic cell loss in Parkinson's disease and MPTP-induced Parkinsonism: sparing of calbindin-D28k-containing cells. Ann N Y Acad Sci 648:42–62
Giaime E, Yamaguchi H, Gautier CA, Kitada T, Shen J (2012) Loss of DJ-1 does not affect mitochondrial respiration but increases ROS production and mitochondrial permeability transition pore opening. PLoS One 7:e40501
Gibb WR1, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry 51:745–752
Gibb WR, Lees AJ (1991) Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson's disease. J Neurol Neurosurg Psychiatry 54:388–396
Giorgio V, Stockum S von, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabo I, Lippe G, Bernardi P (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci U S A 110:5887–5892
Goldberg JA, Guzman JN, Estep CM, Ilijic E, Kondapalli J, Sanchez-Padilla J, Surmeier DJ (2012) Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease. Nat Neurosci 15:1414–1421
Goldberg JH, Fee MS (2012) A cortical motor nucleus drives the basal ganglia-recipient thalamus in singing birds. Nat Neurosci 15:620–627
Gomez-Suaga P, Luzon-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, Hilfiker S (2012) Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet 21:511–525
Grace AA, Bunney BS (1983) Intracellular and extracellular electrophysiology of nigral dopaminergic neurons—1. Identification and characterization. Neuroscience 10:301–315
Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ (2010) Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468:696–700
Hallett PJ, Spoelgen R, Hyman BT, Standaert DG, Dunah AW (2006) Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking. J Neurosci 26:4690–4700
Halliwell B (1992) Oxygen radicals as key mediators in neurological disease: fact or fiction? Ann Neurol 32(Suppl):S10–S15
Hancock DB, Martin ER, Mayhew GM, Stajich JM, Jewett R, Stacy MA, Scott BL, Vance JM, Scott WK (2008) Pesticide exposure and risk of Parkinson's disease: a family-based case-control study. BMC Neurol 8:6
Hassler R (1938) Zur Pathologie der Paralysis agitans und des postenzephalitischen Parkinsonismus. J Psychol Neurol 48:387–476
Heeman B, Van den Haute C, Aelvoet SA, Valsecchi F, Rodenburg RJ, Reumers V, Debyser Z, Callewaert G, Koopman WJ, Willems PH, Baekelandt V (2011) Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance. J Cell Sci 124:1115–1125
Herculano-Houzel S (2009) The human brain in numbers: a linearly scaled-up primate brain. Front Hum Neurosci 3:31
Hernandez-Lopez S, Tkatch T, Perez-Garci E, Galarraga E, Bargas J, Hamm H, Surmeier DJ (2000) D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade. J Neurosci 20:8987–8995
Hettiarachchi NT, Parker A, Dallas ML, Pennington K, Hung CC, Pearson HA, Boyle JP, Robinson P, Peers C (2009) Alpha-synuclein modulation of Ca2+ signaling in human neuroblastoma (SH-SY5Y) cells. J Neurochem 111:1192–1201
Hornykiewicz O (1989) Aging and neurotoxins as causative factors in idiopathic Parkinson's disease—a critical analysis of the neurochemical evidence. Prog Neuropsychopharmacol Biol Psychiatry 13:319–328
Huang H, Tan BZ, Shen Y, Tao J, Jiang F, Sung YY, Ng CK, Raida M, Kohr G, Higuchi M, Fatemi-Shariatpanahi H, Harden B, Yue DT, Soong TW (2012) RNA editing of the IQ domain in Ca(v)1.3 channels modulates their Ca(2)(+)-dependent inactivation. Neuron 73:304–316
Hubble JP, Cao T, Hassanein RE, Neuberger JS, Koller WC (1993) Risk factors for Parkinson's disease. Neurology 43:1693–1697
Hurley MJ, Brandon B, Gentleman SM, Dexter DT (2013) Parkinson's disease is associated with altered expression of CaV1 channels and calcium-binding proteins. Brain 136:2077–2097
Kanaan NM, Manfredsson FP (2012) Loss of functional alpha-synuclein: a toxic event in Parkinson's disease? J Parkinsons Dis 2:249–267
Kanaan NM, Kordower JH, Collier TJ (2007) Age-related accumulation of Marinesco bodies and lipofuscin in rhesus monkey midbrain dopamine neurons: relevance to selective neuronal vulnerability. J Comp Neurol 502:683–700
Kasten M, Klein C (2013) The many faces of alpha-synuclein mutations. Mov Disord 28:697–701
Khaliq ZM, Bean BP (2010) Pacemaking in dopaminergic ventral tegmental area neurons: depolarizing drive from background and voltage-dependent sodium conductances. J Neurosci 30:7401–7413
Kish SJ, Shannak K, Hornykiewicz O (1988) Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. N Engl J Med 318:876–880
Koyano F, Okatsu K, Ishigaki S, Fujioka Y, Kimura M, Sobue G, Tanaka K, Matsuda N (2013) The principal PINK1 and Parkin cellular events triggered in response to dissipation of mitochondrial membrane potential occur in primary neurons. Genes Cells 18:672–681
Kravitz AV, Freeze BS, Parker PR, Kay K, Thwin MT, Deisseroth K, Kreitzer AC (2010) Regulation of Parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466:622–626
Kreitzer AC, Malenka RC (2008) Striatal plasticity and basal ganglia circuit function. Neuron 60:543–554
Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 18:106–108
Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980
Lashuel HA, Petre BM, Wall J, Simon M, Nowak RJ, Walz T, Lansbury PT Jr (2002) Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol 322:1089–1102
Lashuel HA, Overk CR, Oueslati A, Masliah E (2013) The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14:38–48
Lau LM de, Breteler MM (2006) Epidemiology of Parkinson's disease. Lancet Neurol 5:525–535
Lesage S, Brice A (2009) Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 18:R48–R59
Lowe R, Pountney DL, Jensen PH, Gai WP, Voelcker NH (2004) Calcium(II) selectively induces alpha-synuclein annular oligomers via interaction with the C-terminal domain. Protein Sci 13:3245–3252
Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K (2003) The role of alpha-synuclein in Parkinson's disease: insights from animal models. Nat Rev Neurosci 4:727–738
Marongiu R, Spencer B, Crews L, Adame A, Patrick C, Trejo M, Dallapiccola B, Valente EM, Masliah E (2009) Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson's disease by disturbing calcium flux. J Neurochem 108:1561–1574
McDonnell L, McDonnell L, Maginnis C, Lewis S, Pickering N, Antoniak M, Hubbard R, Lawson I, Britton J (2003) Neurology 61:716–717
Melachroinou K, Xilouri M, Emmanouilidou E, Masgrau R, Papazafiri P, Stefanis L, Vekrellis K (2013) Deregulation of calcium homeostasis mediates secreted alpha-synuclein-induced neurotoxicity. Neurobiol Aging 34:2853–2865
Mercuri NB, Bonci A, Calabresi P, Stratta F, Stefani A, Bernardi G (1994) Effects of dihydropyridine calcium antagonists on rat midbrain dopaminergic neurones. Br J Pharmacol 113:831–838
Mortiboys H, Johansen KK, Aasly JO, Bandmann O (2010) Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2. Neurology 75:2017–2020
Mosharov EV, Larsen KE, Kanter E, Phillips KA, Wilson K, Schmitz Y, Krantz DE, Kobayashi K, Edwards RH, Sulzer D (2009) Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 62:218–229
Mouatt-Prigent A, Agid Y, Hirsch EC (1994) Does the calcium binding protein calretinin protect dopaminergic neurons against degeneration in Parkinson's disease? Brain Res 668:62–70
Mutch WJ, Dingwall-Fordyce I, Downie AW, Paterson JG, Roy SK (1986) Parkinson's disease in a Scottish city. Br Med J (Clin Res Ed) 292:534–536
Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803
Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298
Nath S, Goodwin J, Engelborghs Y, Pountney DL (2011) Raised calcium promotes alpha-synuclein aggregate formation. Mol Cell Neurosci 46:516–526
Neafsey EJ, Drucker G, Raikoff K, Collins MA (1989) Striatal dopaminergic toxicity following intranigral injection in rats of 2-methyl-norharman, a beta-carbolinium analog of N-methyl-4-phenylpyridinium ion (MPP+). Neurosci Lett 105:344–349
Neafsey EJ, Albores R, Gearhart D, Kindel G, Raikoff K, Tamayo F, Collins MA (1995) Methyl-beta-carbolinium analogs of MPP + cause nigrostriatal toxicity after substantia nigra injections in rats. Brain Res 675:279–288
Nedergaard S, Flatman JA, Engberg I (1993) Nifedipine- and omega-conotoxin-sensitive Ca2+ conductances in guinea-pig substantia nigra pars compacta neurones. J Physiol (Lond) 466:727–747
Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH (2010) Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65:66–79
Ottolini D, Calì T, Brini M (2013a) Etiology and pathogenesis of Parkinson's disease: role of mitochondrial pathology. Res Rep Biochem 2013:55–70
Ottolini D, Calì T, Negro A, Brini M (2013b) The Parkinson disease-related protein DJ-1 counteracts mitochondrial impairment induced by the tumour suppressor protein p53 by enhancing endoplasmic reticulum-mitochondria tethering. Hum Mol Genet 22:2152–2168
Pakkenberg B, Gundersen HJ (1997) Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 384:312–320
Pakkenberg B, Pelvig D, Marner L, Bundgaard MJ, Gundersen HJ, Nyengaard JR, Regeur L (2003) Aging and the human neocortex. Exp Gerontol 38:95–99
Pakkenberg H, Andersen BB, Burns RS, Pakkenberg B (1995) A stereological study of substantia nigra in young and old rhesus monkeys. Brain Res 693:201–206
Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P (2008) Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci 65:1272–1284
Parsell M (2009) Steven M. Platek, Julian Paul Keenan and Todd K. Shackelford (eds) Evolutionary cognitive neuroscience (book review). Mind Mach 19:275–278
Pasternak B, Svanstrom H, Nielsen NM, Fugger L, Melbye M, Hviid A (2012) Use of calcium channel blockers and Parkinson's disease. Am J Epidemiol 175:627–635
Patron M, Raffaello A, Granatiero V, Tosatto A, Merli G, De Stefani D, Wright L, Pallafacchina G, Terrin A, Mammucari C, Rizzuto R (2013) The mitochondrial calcium uniporter (MCU): molecular identity and physiological roles. J Biol Chem 288:10750–10758
Pelvig DP, Pakkenberg H, Stark AK, Pakkenberg B (2008) Neocortical glial cell numbers in human brains. Neurobiol Aging 29:1754–1762
Petrovitch H, Ross GW, Abbott RD, Sanderson WT, Sharp DS, Tanner CM, Masaki KH, Blanchette PL, Popper JS, Foley D, Launer L, White LR (2002) Plantation work and risk of Parkinson disease in a population-based longitudinal study. Arch Neurol 59:1787–1792
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276:2045–2047
Puopolo M, Raviola E, Bean BP (2007) Roles of subthreshold calcium current and sodium current in spontaneous firing of mouse midbrain dopamine neurons. J Neurosci 27:645–656
Redgrave P, Prescott TJ, Gurney K (1999) The basal ganglia: a vertebrate solution to the selection problem? Neuroscience 89:1009–1023
Ren H, Fu K, Wang D, Mu C, Wang G (2011) Oxidized DJ-1 interacts with the mitochondrial protein BCL-XL. J Biol Chem 286:35308–35317
Ren H, Fu K, Mu C, Zhen X, Wang G (2012) L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-XL. Mol Neurodegener 7:40
Reznichenko L, Cheng Q, Nizar K, Gratiy SL, Saisan PA, Rockenstein EM, Gonzalez T, Patrick C, Spencer B, Desplats P, Dale AM, Devor A, Masliah E (2012) In vivo alterations in calcium buffering capacity in transgenic mouse model of synucleinopathy. J Neurosci 32:9992–9998
Ritz B, Rhodes SL, Qian L, Schernhammer E, Olsen JH, Friis S (2010) L-type calcium channel blockers and Parkinson disease in Denmark. Ann Neurol 67:600–606
Ross CA, Poirier MA (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol 6:891–898
Schapira AH (2011) Mitochondrial pathology in Parkinson's disease. Mt Sinai J Med 78:872–881
Schmidt F, Levin J, Kamp F, Kretzschmar H, Giese A, Botzel K (2012) Single-channel electrophysiology reveals a distinct and uniform pore complex formed by alpha-synuclein oligomers in lipid membranes. PLoS One 7:e42545
Schwaller B (2012) The use of transgenic mouse models to reveal the functions of Ca2+ buffer proteins in excitable cells. Biochim Biophys Acta 1820:1294–1303
Seidler A, Hellenbrand W, Robra BP, Vieregge P, Nischan P, Joerg J, Oertel WH, Ulm G, Schneider E (1996) Possible environmental, occupational, and other etiologic factors for Parkinson's disease: a case-control study in Germany. Neurology 46:1275–1284
Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25:302–305
Shtifman A, Zhong N, Lopez JR, Shen J, Xu J (2011) Altered Ca2+ homeostasis in the skeletal muscle of DJ-1 null mice. Neurobiol Aging 32:125–132
Sibley DR (1995) Molecular biology of dopamine receptors. In: Surmeier DJ, Ariano MA (eds) Molecular and cellular mechanisms of the neostriatal function. Landes, Austin, pp 255-272
Smith Y, Raju DV, Pare JF, Sidibe M (2004) The thalamostriatal system: a highly specific network of the basal ganglia circuitry. Trends Neurosci 27:520–527
Snyder GL, Allen PB, Fienberg AA, Valle CG, Huganir RL, Nairn AC, Greengard P (2000) Regulation of phosphorylation of the GluR1 AMPA receptor in the neostriatum by dopamine and psychostimulants in vivo. J Neurosci 20:4480–4488
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840
Steiner H, Tseng KY (2010) Handbook of basal ganglia structure and function: a decade of progress. Elsevier Science, Amsterdam
Sterky FH, Lee S, Wibom R, Olson L, Larsson NG (2011) Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo. Proc Natl Acad Sci U S A 108:12937–12942
Surmeier DJ (2007) Calcium, aging, and neuronal vulnerability in Parkinson's disease. Lancet Neurol 6:933–938
Surmeier DJ, Schumacker PT (2013) Calcium, bioenergetics, and neuronal vulnerability in Parkinson's disease. J Biol Chem 288:10736–10741
Surmeier DJ, Bargas J, Hemmings HC Jr, Nairn AC, Greengard P (1995) Modulation of calcium currents by a D1 dopaminergic protein kinase/phosphatase cascade in rat neostriatal neurons. Neuron 14:385–397
Surmeier DJ, Guzman JN, Sanchez J, Schumacker PT (2012) Physiological phenotype and vulnerability in Parkinson's disease. Cold Spring Harb Perspect Med 2:a009290
Takahashi H, Ohama E, Suzuki S, Horikawa Y, Ishikawa A, Morita T, Tsuji S, Ikuta F (1994) Familial juvenile Parkinsonism: clinical and pathologic study in a family. Neurology 44:437–441
Tanner CM, Ross GW, Jewell SA, Hauser RA, Jankovic J, Factor SA, Bressman S, Deligtisch A, Marras C, Lyons KE, Bhudhikanok GS, Roucoux DF, Meng C, Abbott RD, Langston JW (2009) Occupation and risk of Parkinsonism: a multicenter case-control study. Arch Neurol 66:1106–1113
Tateno T, Harsch A, Robinson HP (2004) Threshold firing frequency-current relationships of neurons in rat somatosensory cortex: type 1 and type 2 dynamics. J Neurophysiol 92:2283–2294
Tolleson CM, Fang JY (2013) Advances in the mechanisms of Parkinson's disease. Discov Med 15:61–66
Trinh J, Farrer M (2013) Advances in the genetics of Parkinson disease. Nat Rev Neurol 9:445–454
Tsigelny IF, Sharikov Y, Wrasidlo W, Gonzalez T, Desplats PA, Crews L, Spencer B, Masliah E (2012) Role of alpha-synuclein penetration into the membrane in the mechanisms of oligomer pore formation. FEBS J 279:1000–1013
Uhl GR, Hedreen JC, Price DL (1985) Parkinson's disease: loss of neurons from the ventral tegmental area contralateral to therapeutic surgical lesions. Neurology 35:1215–1218
Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304:1158–1160
Van Laar VS, Arnold B, Cassady SJ, Chu CT, Burton EA, Berman SB (2011) Bioenergetics of neurons inhibit the translocation response of Parkin following rapid mitochondrial depolarization. Hum Mol Genet 20:927–940
Vilchis C, Bargas J, Ayala GX, Galvan E, Galarraga E (2000) Ca2+ channels that activate Ca2+-dependent K+ currents in neostriatal neurons. Neuroscience 95:745–752
Wichmann T, DeLong MR (2003) Functional neuroanatomy of the basal ganglia in Parkinson's disease. Adv Neurol 91:9–18
Wilson MA (2011) The role of cysteine oxidation in DJ-1 function and dysfunction. Antioxid Redox Signal 15:111–122
Xu W, Lipscombe D (2001) Neuronal Ca(V)1.3alpha(1) L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J Neurosci 21:5944–5951
Yamada T, McGeer PL, Baimbridge KG, McGeer EG (1990) Relative sparing in Parkinson's disease of substantia nigra dopamine neurons containing calbindin-D28K. Brain Res 526:303–307
Yankner BA, Lu T, Loerch P (2008) The aging brain. Annu Rev Pathol 3:41–66
Yao Z, Gandhi S, Burchell VS, Plun-Favreau H, Wood NW, Abramov AY (2011) Cell metabolism affects selective vulnerability in PINK1-associated Parkinson's disease. J Cell Sci 124:4194–4202
Ying Z, Lin F, Gu W, Su Y, Arshad A, Qing H, Deng Y (2011) Alpha-synuclein increases U251 cells vulnerability to hydrogen peroxide by disrupting calcium homeostasis. J Neural Transm 118:1165–1172
Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12:9–14
Author information
Authors and Affiliations
Corresponding author
Additional information
The original work by the authors has been supported over the years by grants from the Italian Ministry of University and Research (PRIN 2003, 2005, and 2008), the Telethon Foundation (Project GGP04169), the Italian National Research Council (Agenzia 2000, CNR), and the University of Padova (Progetto di Ateneo 2008 CPDA082825) to M.B. Tito Calì is supported by the University of Padova (Progetto Giovani GRIC128SP0, Bando 2012).
Rights and permissions
About this article
Cite this article
Calì, T., Ottolini, D. & Brini, M. Calcium signaling in Parkinson’s disease. Cell Tissue Res 357, 439–454 (2014). https://doi.org/10.1007/s00441-014-1866-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-014-1866-0