Niemann Pick type C (NPC) is a rare neurovisceral disorder characterized by progressive hepatosplenomegaly, neurodegeneration, and premature death; it is caused by mutations in genes coding for two lysosomal proteins: the transmembrane NPC1 and the soluble NPC2. Mutations in both of them cause intracellular accumulation of cholesterol and other lipids in the endo/lysosomal compartment. Currently, an inhibitor of glycosphingolipid synthesis is the only drug approved by the European Medicines Agency, but it only reduces rate of disease progression; for this reason, the search for new druggable targets is urgent. In the present review, the adenosinergic system with a particular focus onto the adenosine A2A receptor will be presented as a potential therapeutic target for NPC and results obtained in cellular and animal models of the disease will be discussed.
WassifCA, CrossJL, IbenJ, et al.High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets. Genet Med. 2016; 18:41–48.
3.
PattersonMC, ClaytonP, GissenP, et al.Recommendations for the detection and diagnosis of Niemann-Pick disease type C: An update. Neurol Clin Pract. 2017; 7:499–511.
4.
CarsteaED, MorrisJA, ColemanKG, et al.Niemann-Pick C1 disease gene: Homology to mediators of cholesterol homeostasis. Science. 1997; 277:228–231.
5.
PinedaM, WalterfangM, PattersonMC. Miglustat in Niemann-Pick disease type C patients: A review. Orphanet J Rare Dis. 2018; 13:140.
6.
VanierMT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010; 5:16.
7.
PattersonMC, HendrikszCJ, WalterfangM, et al.Recommendations for the diagnosis and management of Niemann-Pick disease type C: An update. Mol Genet Metab. 2012; 106:330–344.
8.
ImrieJ, VijayaraghavenS, WhitehouseC, et al.Niemann-Pick disease type C in adults. J Inherit Metab Dis. 2002; 25:491–500.
9.
BonnotO, GamaCS, MengelE, et al.Psychiatric and neurological symptoms in patients with Niemann-Pick disease type C (NP-C): Findings from the International NPC Registry. World J Biol Psychiatry. 2019; 20:310–319.
10.
LoveS, BridgesLR, CaseCP. Neurofibrillary tangles in Niemann-Pick disease type C. Brain. 1995; 118:119–129.
11.
KartenB, PeakeKB, VanceJE. Mechanisms and consequences of impaired lipid trafficking in Niemann–Pick type C1-deficient mammalian cells. Biochim Biophys Acta. 2009; 1791:659–670.
12.
WalterfangM, FaheyM, DesmondP, et al.White and gray matter alterations in adults with Niemann-Pick disease type C: A cross-sectional study. Neurology. 2010; 75:49–56.
13.
KennedyBE, LeBlancVG, MailmanTM, et al.Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in niemann-pick type C1-deficient murine brain. PLoS One. 2013; 8:e82685.
14.
YuT, LiebermanAP. Npc1 Acting in Neurons and Glia Is Essential for the Formation and Maintenance of CNS Myelin. PLoS Genet. 2013; 9:e1003462.
15.
WalterfangM, FaheyM, AbelL, et al.Size and shape of the corpus callosum in adult niemann-pick type C reflects state and trait illness variables. Am J Neuroradiol. 2011; 32:1340–1346.
16.
WalterfangM, PatenaudeB, AbelLA, et al.Subcortical volumetric reductions in adult niemann-pick disease type C: A cross-sectional study. Am J Neuroradiol. 2013; 34:1334–1340.
17.
AbelLA, WalterfangM, StainerMJ, et al.Longitudinal assessment of reflexive and volitional saccades in Niemann-Pick Type C disease during treatment with miglustat. Orphanet J Rare Dis. 2015; 10:160.
18.
Lloyd-EvansE, PlattFM. Lipids on trial: The search for the offending metabolite in Niemann-Pick type C disease. Traffic. 2010; 11:419–428.
19.
Lloyd-EvansE, MorganAJ, HeX, et al.Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med. 2008; 14:1247–1255.
20.
YuW, GongJ-S, KoM, et al.Altered cholesterol metabolism in niemann-pick type C1 mouse brains affects mitochondrial function. J Biol Chem. 2005; 280:11731–11739.
21.
KennedyBE, MadreiterCT, VishnuN, et al.Adaptations of energy metabolism associated with increased levels of mitochondrial cholesterol in Niemann-Pick type C1-deficient cells. J Biol Chem. 2014; 289:16278–16289.
22.
WośM, SzczepanowskaJ, PikułaS, et al.Mitochondrial dysfunction in fibroblasts derived from patients with Niemann-Pick type C disease. Arch Biochem Biophys. 2016; 593:50–59.
23.
TorresS, MatíasN, BauliesA, et al.Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease. Redox Biol. 2017; 11:60–72.
24.
OrdonezMP, RobertsEA, KidwellCU, et al.Disruption and therapeutic rescue of autophagy in a human neuronal model of Niemann Pick type C1. Hum Mol Genet. 2012; 21:2651–2662.
25.
CrockerAC, FarberS. Niemann-Pick disease: A review of eighteen patients. Medicine (Baltimore). 1958; 37:1–95.
26.
RibeiroJA, SebastiãoAM, de MendonçaA. Adenosine receptors in the nervous system: Pathophysiological implications. Prog Neurobiol. 2002; 68:377–392.
27.
GomesCV, KasterMP, ToméAR, et al.Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration. Biochim Biophys Acta, 2011; 1808:1380–1399.
28.
SolimanAM, FathallaAM, MoustafaAA. Adenosine role in brain functions: Pathophysiological influence on Parkinson's disease and other brain disorders. Pharmacol Rep. 2018; 70:661–667.
29.
HaskóG, PacherP, Sylvester ViziE, et al.Adenosine receptor signaling in the brain immune system. Trends Pharmacol Sci. 2005; 26:511–516.
30.
ParkinsonFE, DamarajuVL, GrahamK, et al.Molecular biology of nucleoside transporters and their distributions and functions in the brain. Curr Top Med Chem. 2011; 11:948–972.
31.
BurnstockG. Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev. 2007; 87:659–797.
32.
ZimmermannH, ZebischM, SträterN. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal. 2012; 8:437–502.
33.
FredholmBB, IJzermanAP, JacobsonKA, et al.International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update. Pharmacol Rev. 2011; 63:1–34.
34.
FredholmBB, ChernY, FrancoR, et al.Aspects of the general biology of adenosine A2A signaling. Prog Neurobiol. 2007; 83:263–276.
35.
PinnaA, SerraM, MorelliM, et al.Role of adenosine A2A receptors in motor control: Relevance to Parkinson's disease and dyskinesia. J Neural Transm. 2018; 125:1273–1286.
36.
OrrAG, HsiaoEC, WangMM, et al.Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat Neurosci. 2015; 18:423–434.
37.
BlumD, ChernY, DomeniciMR, et al.The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease. J Caffeine Adenosine Res. 2018; 8:43–58.
38.
LeivaA, Guzmán-GutiérrezE, Contreras-DuarteS, et al.Adenosine receptors: Modulators of lipid availability that are controlled by lipid levels. Mol Aspects Med. 2017; 55:26–44.
39.
ReissAB, RahmanMM, ChanESL, et al.Adenosine A2A receptor occupancy stimulates expression of proteins involved in reverse cholesterol transport and inhibits foam cell formation in macrophages. J Leukoc Biol. 2004; 76:727–734.
40.
CariniR, CastinoR, De CesarisMG, et al.Preconditioning-induced cytoprotection in hepatocytes requires Ca2+-dependent exocytosis of lysosomes. J Cell Sci. 2004; 117:1065–1077.
41.
LiuJ, LuW, ReigadaD, et al.Restoration of lysosomal pH in RPE cells from cultured human and ABCA4 −/− mice: Pharmacologic approaches and functional recovery. Invest Opthalmol Vis Sci. 2008; 49:772.
42.
ChristensenKA, MyersJT, SwansonJA. pH-dependent regulation of lysosomal calcium in macrophages. J Cell Sci. 2002; 115:599–607.
43.
ZhouS, XuS, YanY, et al.Decreased purinergic inhibition of synaptic activity in a mouse model of Niemann-Pick disease type C. Hippocampus. 2011; 21:212–219.
44.
MalenkaRC. The long-term potential of LTP. Nat Rev Neurosci. 2003; 4:923–926.
45.
LynchMA. Long-term potentiation and memory. Physiol Rev. 2004; 84:87–136.
46.
VisentinS, De NuccioC, BernardoA, et al.The stimulation of adenosine A2A receptors ameliorates the pathological phenotype of fibroblasts from Niemann-Pick type C patients. J Neurosci. 2013; 33:15388–15393.
47.
FerranteA, De NuccioC, PepponiR, et al.Stimulation of adenosine A2A receptors reduces intracellular cholesterol accumulation and rescues mitochondrial abnormalities in human neural cell models of Niemann-Pick C1. Neuropharmacology. 2016; 103:155–162.
48.
TakikitaS, FukudaT, MohriI, et al.Perturbed myelination process of premyelinating oligodendrocyte in Niemann-Pick type C mouse. J Neuropathol Exp Neurol. 2004; 63:660–673.
49.
KodachiT, MatsumotoS, MizuguchiM, et al.Severe demyelination in a patient with a late infantile form of Niemann-Pick disease type C. Neuropathology. 2017; 37:426–430.
50.
De NuccioC, BernardoA, FerranteA, et al.Adenosine A2A receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes. Sci Rep. 2019; 9:9782.
51.
FerranteA, PezzolaA, MatteucciA, et al.The adenosine A 2A receptor agonist T1–T11 ameliorates neurovisceral symptoms and extends the lifespan of a mouse model of Niemann-Pick type C disease. Neurobiol Dis. 2018; 110:1–11.
52.
HuangN-K, LinJ-H, LinJ-T, et al.A new drug design targeting the adenosinergic system for Huntington's disease. PLoS One. 2011; 6:e20934.
53.
ChouA-H, ChenY-L, ChiuC-C, et al.T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse. Neuropharmacology. 2015; 99:308–317.
54.
WebbRL, BarclayBW, GraybillSC. Cardiovascular effects of adenosine A2 agonists in the conscious spontaneously hypertensive rat: A comparative study of three structurally distinct ligands. J Pharmacol Exp Ther. 1991; 259:1203–1212.
