Skip to main content
SpringerLink
Log in

Pericytes in Neurometabolic Diseases

  • Pericytes (A Birbrair, Section Editor)
  • Published:
Current Tissue Microenvironment Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Since brain pericytes guarantee appropriate development and maintenance of the cerebrovascular system, we reviewed their role in neurometabolic diseases (NMDs), a subclass of inborn errors of metabolism that selectively cause neurological sequels and widespread cerebrovascular alterations.

Recent Findings

Main findings about pericyte involvement in NMDs arise from glutaric acidemia type I (GA-I) models. In this regard, we found that (i) a single intracisternal injection of the main accumulated metabolite (glutaric acid, GA) in rat neonates disturbed the neurovascular unit (NVU) as evidenced by blood-brain barrier hyperpermeability, and altered immunoreactivity of pericyte and astrocyte markers surrounding brain microvessels; (ii) GA-elicited capillary constriction near pericyte somata likely inducing reduced brain blood flow as reported in GA-I patients; (iii) GA-elicited pericyte contraction probably results from a defective interplay among NVU components and could be relevant in case of metabolic decompensation or energetic deficiency.

Summary

Although pericyte pathological features have been studied in few NMDs, their involvement in NMD pathophysiology is largely unknown. Thus, further studies are needed to identify their roles and therapeutic potentiality.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Harris H. Garrod’s inborn errors of metabolism. London: Oxford University Press; 1963.

    Google Scholar 

  2. De Meirleir L, Rodan LH. Approach to the patient with a metabolic disorder. In: Swaiman KF, Ferriero DM, Finkel RS, Pearl PL, Ashwal S, Schor NF, Gropman AL, Shevell MI, editors. Swaiman’s pediatric neurology, principles and practice. 6th ed. London: Elsevier; 2017.

    Google Scholar 

  3. Agana M, Frueh J, Kamboj M, Patel DR, Kanungo S. Common metabolic disorder (inborn errors of metabolism) concerns in primary care practice. Ann Transl Med. 2018;6(24):469. https://doi.org/10.21037/atm.2018.12.34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Ferreira CR, van Karnebeek CDM, Vockley J, Blau N. A proposed nosology of inborn errors of metabolism. Genet Med. 2019;21(1):102–6. https://doi.org/10.1038/s41436-018-0022-8.

    Article  PubMed  Google Scholar 

  5. •• Saudubray JM, Garcia-Cazorla A. An overview of inborn errors of metabolism affecting the brain: from neurodevelopment to neurodegenerative disorders. Dialogues Clin Neurosci. 2018;20:301–25.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Burlina AP. Preface. In: Burlina AP, editor. Neurometabolic hereditary diseases of adults. Switzerland: Springer Nature; 2017.

    Google Scholar 

  7. Burlina AP, Polo G. Screening population for neurological inherited metabolic diseases. In: Burlina AP, editor. Neurometabolic hereditary diseases of adults. Switzerland: Springer Nature; 2017.

    Google Scholar 

  8. Manara R, Burlina AP. Neuroimaging of inherited metabolic diseases of adulthood. In: Burlina AP, editor. Neurometabolic hereditary diseases of adults. Switzerland: Springer Nature; 2017.

    Google Scholar 

  9. Carson NAJ. Homocystinuria: clinical and biochemical heterogeneity. In: Cockburn F, Gitzelmann R, editors. Inborn errors of metabolism in humans. Lancaster: MTP Press Limited; 1982.

    Google Scholar 

  10. Erol M, Gayret OB, Yigit O, Cabuk KS, Toksoz M, Tiras M. A case of homocystinuria misdiagnosed as moyamoya disease: a case report. Iran Red Crescent Med J. 2016;18(4):e30332. https://doi.org/10.5812/ircmj.30332.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic bases of inherited disease. 8th ed. New York: MacGraw-Hill; 2001.

    Google Scholar 

  12. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. https://doi.org/10.1186/1750-1172-5-30.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Desnick RJ. Prenatal diagnosis of Fabry disease. Prenat Diagn. 2007;27(8):693–4. https://doi.org/10.1002/pd.1767.

    Article  PubMed  Google Scholar 

  14. Thurberg BL, Politei JM. Histologic abnormalities of placental tissues in Fabry disease: a case report and review of the literature. Hum Pathol. 2012;43(4):610–4. https://doi.org/10.1016/j.humpath.2011.07.020.

    Article  PubMed  Google Scholar 

  15. Baptista MV, Ferreira S, Pinho-E-Melo T, Carvalho M, Cruz VT, Carmona C, et al. Mutations of the GLA gene in young patients with stroke: the PORTYSTROKE study—screening genetic conditions in Portuguese young stroke patients. Stroke. 2010;41:431–6. https://doi.org/10.1161/STROKEAHA.109.570499.

    Article  PubMed  CAS  Google Scholar 

  16. Chang YH, Hwang SK. A case of cerebral aneurysmal subarachnoid hemorrhage in Fabry’s disease. J Korean Neurosurg Soc. 2013;53(3):187–9. https://doi.org/10.3340/jkns.2013.53.3.187.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cormican MT, Paschalis T, Viers A, Alleyne CH Jr. Unusual case of subarachnoid haemorrhage in patient with Fabry’s disease: case report and literature review. BMJ Case Rep. 2012;2012:bcr0220125727. https://doi.org/10.1136/bcr.02.2012.5727.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kolodny E, Fellgiebel A, Hilz MJ, Sims K, Caruso P, Phan TG, et al. Cerebrovascular involvement in Fabry disease: current status of knowledge. Stroke. 2015;46:302–13. https://doi.org/10.1161/STROKEAHA.114.006283.

    Article  PubMed  Google Scholar 

  19. Kono Y, Wakabayashi T, Kobayashi M, Ohashi T, Eto Y, Ida H, et al. Characteristics of cerebral microbleeds in patients with Fabry disease. J Stroke Cerebrovasc Dis. 2016;25:1320–5. https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.02.019.

    Article  PubMed  Google Scholar 

  20. Mehta A, Ginsberg L, FOS Investigators. Natural history of the cerebrovascular complications of Fabry disease. Acta Paediatr Suppl. 2005;94(447):24–7. https://doi.org/10.1111/j.1651-2227.2005.tb02106.x.

    Article  PubMed  CAS  Google Scholar 

  21. Sims K, Politei J, Banikazemi M, Lee P. Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry. Stroke. 2009;40:788–94. https://doi.org/10.1161/STROKEAHA.108.526293.

    Article  PubMed  Google Scholar 

  22. Murphy AP, Straub V. Pompe disease. In: Burlina AP, editor. Neurometabolic hereditary diseases of adults. Switzerland: Springer Nature; 2017.

    Google Scholar 

  23. Testai FD, Gorelick PB. Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders. Arch Neurol. 2010;67(2):148–53. https://doi.org/10.1001/archneurol.2009.333.

    Article  PubMed  Google Scholar 

  24. Ferreira CR, van Karnebeek CDM. Inborn errors of metabolism. Handb Clin Neurol. 2019;162:449–81. https://doi.org/10.1016/B978-0-444-64029-1.00022-9.

    Article  PubMed  Google Scholar 

  25. Dave P, Curless RG, Steinman L. Cerebellar hemorrhage complicating methylmalonic and propionic acidemia. Arch Neurol. 1984;41(12):1293–6. https://doi.org/10.1001/archneur.1984.04050230079025.

    Article  PubMed  CAS  Google Scholar 

  26. Fischer AQ, Challa VR, Burton BK, McLean WT. Cerebellar hemorrhage complicating isovaleric acidemia: a case report. Neurology. 1981;31(6):746–8. https://doi.org/10.1212/wnl.31.6.746.

    Article  PubMed  CAS  Google Scholar 

  27. Haas RH, Marsden DL, Capistrano-Estrada S, Hamilton R, Grafe MR, Wong W, et al. Acute basal ganglia infarction in propionic acidemia. J Child Neurol. 1995;10(1):18–22. https://doi.org/10.1177/088307389501000104.

    Article  PubMed  CAS  Google Scholar 

  28. Chemelli AP, Schocke M, Sperl W, Trieb T, Aichner F, Felber S. Magnetic resonance spectroscopy (MRS) in five patients with treated propionic acidemia. J Magn Reson Imaging. 2000;11(6):596–600. https://doi.org/10.1002/1522-2586(200006)11:6<596::aid-jmri4>3.0.co;2-p.

    Article  PubMed  CAS  Google Scholar 

  29. Trinh BC, Melhem ER, Barker PB. Multi-slice proton spectroscopy and diffusion weighted imaging in methylmalonic acidemia: report of two cases and review of the literature. AJNR Am J Neuroradiol. 2001;22(5):831–3.

    PubMed  CAS  Google Scholar 

  30. Bergman AJ, Van der Knaap MS, Smeitink JA, Duran M, Dorland L, Valk J, et al. Magnetic resonance imaging and spectroscopy of the brain in propionic acidemia: clinical and biochemical considerations. Pediatr Res. 1996;40(3):404–9. https://doi.org/10.1203/00006450-199609000-00007.

    Article  PubMed  CAS  Google Scholar 

  31. Goodman SI, Moe PG, Markey SP, O’Brien D. Glutaric aciduria; a “new” disorder of amino acid metabolism. Biochem Med. 1975;12(1):12–21. https://doi.org/10.1203/00006450-197404000-00295.

    Article  PubMed  CAS  Google Scholar 

  32. Hoffmann GF, Athanassopoulos S, Burlina AB, Duran M, de Klerk JB, Lehnert W, et al. Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics. 1996;27(3):115–23. https://doi.org/10.1055/s-2007-973761.

    Article  PubMed  CAS  Google Scholar 

  33. Larson A, Goodman S: Glutaric acidemia type 1. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. Seattle:GeneReviews®, 2019.

  34. Goldfarb DS, Kenny J-E S. Metabolic acidosis. In: Lerma EV, Sparks MA, Topf JM, editors. Nephrology secrets. 1st South Asia ed. India: Elsevier; 2017.

    Google Scholar 

  35. Clarke JTR. A clinical guide to inherited metabolic diseases. 3rd ed. Cambridge: Cambridge University Press; 2005.

    Book  Google Scholar 

  36. Saudubray J-M, Desguerre I, Sedel F, Charpentier C. A clinical approach to inherited metabolic diseases. In: Fernandes J, Saudubray J-M, van den Berghe G, Walter JH, editors. Inborn metabolic diseases, 4th. revised ed. Berlin: Springer; 2006.

    Google Scholar 

  37. Hoffmann GF, Gibson KM, Trefz FK, Nyhan WL, Bremer HJ, Rating D. Neurological manifestations of organic acid disorders. Eur J Pediatr. 1994;153(7 Suppl1):S94–100. https://doi.org/10.1007/BF02138786.

    Article  PubMed  CAS  Google Scholar 

  38. Zinnanti WJ, Lazovic J, Housman C, Antonetti DA, Koeller DM, Connor JR, et al. Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I. Acta Neuropathol Commun. 2014;2:13. https://doi.org/10.1186/2051-5960-2-13.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Berthiaume AA, Hartmann DA, Majesky MW, Bhat NR, Shih AY. Pericyte structural remodeling in cerebrovascular health and homeostasis. Front Aging Neurosci. 2018;10:210. https://doi.org/10.3389/fnagi.2018.00210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. • Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci. 2016;19(6):771–83. https://doi.org/10.1038/nn.4288A comprehensive review of pericytes physiology and signaling in the neurovascular unit as well as about their roles in CNS disorders.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain barrier: from physiology to disease and back. Physiol Rev. 2019;99(1):21–78. https://doi.org/10.1152/physrev.00050.2017.

    Article  PubMed  CAS  Google Scholar 

  42. Hall CN, Reynell C, Gesslein B, Mishra A, Sutherland BA, O'Farrell FM, et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014;508:55–60. https://doi.org/10.1038/nature13165.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Hill RA, Tong L, Yuan P, Murikinati S, Gupta S, Grutzendler J. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron. 2015;87:95–110. https://doi.org/10.1016/j.neuron.2015.06.001.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectional control of CNS capillary diameter by pericytes. Nature. 2006;443(7112):700–4. https://doi.org/10.1038/nature05193.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Fernandez-Klett F, Potas JR, Hilpert D, Blazej K, Radke J, Huck J, et al. Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke. J Cereb Blood Flow Metab. 2013;33:428–39. https://doi.org/10.1038/jcbfm.2012.187.

    Article  PubMed  CAS  Google Scholar 

  46. Armulik A, Genove G, Mae M, Wallgard E, Niaudet C, He L, et al. Pericytes regulate the blood–brain barrier. Nature. 2010;468(7323):557–61. https://doi.org/10.1038/nature09522.

    Article  PubMed  CAS  Google Scholar 

  47. Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010;68:409–27. https://doi.org/10.1016/j.neuron.2010.09.043.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature. 2010;68:562–6. https://doi.org/10.1038/nature09513.

    Article  CAS  Google Scholar 

  49. Cheng J, Korte N, Nortley R, Sethi H, Tang Y, Attwell D. Targeting pericytes for therapeutic approaches to neurological disorders. Acta Neuropathol. 2018;l136:507–23. https://doi.org/10.1007/s00401-018-1893-0.

    Article  CAS  Google Scholar 

  50. Funk CB, Prasad AN, Frosk P, Sauer S, Kölker S, Greenberg CR, et al. Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain. 2005;128(4):711–22. https://doi.org/10.1093/brain/awh401.

    Article  PubMed  Google Scholar 

  51. Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF. Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable-isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis. 1999;22(8):867–81. https://doi.org/10.1023/a:1005683222187.

    Article  PubMed  CAS  Google Scholar 

  52. Christensen E, Ribes A, Merinero B, Zschocke J. Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2004;27(6):861–8. https://doi.org/10.1023/B:BOLI.0000045770.93429.3c.

    Article  PubMed  CAS  Google Scholar 

  53. Kölker S, Garbade SF, Greenberg CR, Leonard JV, Saudubray JM, Ribes A, et al. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res. 2006;59(6):840–7. https://doi.org/10.1203/01.pdr.0000219387.79887.86.

    Article  PubMed  Google Scholar 

  54. Kölker S, Christensen E, Leonard JV, Greenberg CR, Boneh A, Burlina AB, et al. Diagnosis and management of glutaric aciduria type I-revised recommendations. J Inherit Metab Dis. 2011;34(3):677–94. https://doi.org/10.1007/s10545-011-9289-5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Harting I, Neumaier-Probst E, Seitz A, Maier EM, Assmann B, Baric I, et al. Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain. 2009;132(Pt 7):1764–82. https://doi.org/10.1093/brain/awp112.

    Article  PubMed  Google Scholar 

  56. Strauss KA, Puffenberger EG, Robinson DL, Morton DH. Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet C: Semin Med Genet. 2003;121C(1):38–52. https://doi.org/10.1002/ajmg.c.20007.

    Article  Google Scholar 

  57. Knapp JF, Soden SE, Dasouki MJ, Walsh IR. A 9-month-old baby with subdural hematomas, retinal hemorrhages, and developmental delay. Pediatr Emerg Care. 2002;18(1):44–7. https://doi.org/10.1097/00006565-200202000-00014.

    Article  PubMed  Google Scholar 

  58. Twomey EL, Naughten ER, Donoghue VB, Ryan S. Neuroimaging findings in glutaric aciduria type 1. Pediatr Radiol. 2003;33(12):823–30. https://doi.org/10.1007/s00247-003-0956-z.

    Article  PubMed  Google Scholar 

  59. Neumaier-Probst E, Harting I, Seitz A, Ding C, Kolker S. Neuroradiological findings in glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency). J Inherit Metab Dis. 2004;27(6):869–76. https://doi.org/10.1023/B:BOLI.0000045771.66300.2a.

    Article  PubMed  CAS  Google Scholar 

  60. Singh P, Goraya JS, Ahluwalia A, Saggar K. Teaching neuroimages: Glutaric aciduria type 1 (glutaryl-CoA dehydrogenase deficiency). Neurology. 2011;77(1):e6. https://doi.org/10.1212/WNL.0b013e31822313f6.

    Article  PubMed  Google Scholar 

  61. Lindner M, Kölker S, Schulze A, Christensen E, Greenberg CR, Hoffmann GF. Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2004;27(6):851–9. https://doi.org/10.1023/B:BOLI.0000045769.96657.af.

    Article  PubMed  CAS  Google Scholar 

  62. Morton DH, Bennett MJ, Seargeant LE, Nichter CA, Kelley RI. Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am J Med Genet. 1991;41(1):89–95. https://doi.org/10.1002/ajmg.1320410122.

    Article  PubMed  CAS  Google Scholar 

  63. Haworth JC, Dilling LA, Seargeant LE. Increased prevalence of hereditary metabolic diseases among native Indians in Manitoba and northwestern Ontario. CMAJ. 1991;145(2):123–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  64. Basinger AA, Booker JK, Frazier DM, Koeberl DD, Sullivan JA, Muenzer J. Glutaric acidemia type 1 in patients of Lumbee heritage from North Carolina. Mol Genet Metab. 2006;88(1):90–2. https://doi.org/10.1016/j.ymgme.2005.12.008.

    Article  PubMed  CAS  Google Scholar 

  65. Monavari AA, Naughten ER. Prevention of cerebral palsy in glutaric aciduria type 1 by dietary management. Arch Dis Child. 2000;82(1):67–70. https://doi.org/10.1136/adc.82.1.67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Boy N, Mengler K, Thimm E, Schiergens KA, Marquardt T, Weinhold N, et al. Newborn screening: a disease-changing intervention for glutaric aciduria type 1. Ann Neurol. 2018;83(5):970–9. https://doi.org/10.1002/ana.25233.

    Article  PubMed  CAS  Google Scholar 

  67. • Boy N, Mühlhausen C, Maier EM, Heringer J, Assmann B, Burgard P, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75–101. https://doi.org/10.1007/s10545-016-9999-9A comprehensive and up-to-date review about the diagnosis and management of GA-I patients.

    Article  PubMed  Google Scholar 

  68. Strauss KA, Brumbaugh J, Duffy A, Wardley B, Robinson D, Hendrickson C, et al. Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency: focus on cerebral amino acid influx. Mol Genet Metab. 2011;104(1–2):93–106. https://doi.org/10.1016/j.ymgme.2011.07.003.

    Article  PubMed  CAS  Google Scholar 

  69. Viau K, Ernst SL, Vanzo RJ, Botto LD, Pasquali M, Longo N. Glutaric acidemia type 1: outcomes before and after expanded newborn screening. Mol Genet Metab. 2012;106(4):430–8. https://doi.org/10.1016/j.ymgme.2012.05.024.

    Article  PubMed  CAS  Google Scholar 

  70. Couce ML, López-Suárez O, Bóveda MD, Castiñeiras DE, Cocho JA, García-Villoria J, et al. Glutaric aciduria type I: outcome of patients with early- versus late-diagnosis. Eur J Paediatr Neurol. 2013;17(4):383–9. https://doi.org/10.1016/j.ejpn.2013.01.003.

    Article  PubMed  Google Scholar 

  71. Beauchamp MH, Boneh A, Anderson V. Cognitive, behavioural and adaptive profiles of children with glutaric aciduria type I detected through newborn screening. J Inherit Metab Dis. 2009;32(Suppl 1):S207–13. https://doi.org/10.1007/s10545-009-1167-z.

    Article  PubMed  Google Scholar 

  72. Jafari P, Braissant O, Bonafé L, Ballhausen D. The unsolved puzzle of neuropathogenesis in glutaric aciduria type I. Mol Genet Metab. 2011;104(4):425–37. https://doi.org/10.1016/j.ymgme.2011.08.027.

    Article  PubMed  CAS  Google Scholar 

  73. Herskovitz M, Goldsher D, Sela BA, Mandel H. Subependymal mass lesions and peripheral polyneuropathy in adult-onset glutaric aciduria type I. Neurology. 2013;81(9):849–50. https://doi.org/10.1212/WNL.0b013e3182a2cbf2.

    Article  PubMed  Google Scholar 

  74. du Moulin M, Thies B, Blohm M, Oh J, Kemper MJ, Santer R. Glutaric aciduria type 1 and acute renal failure: case report and suggested pathomechanisms. JIMD Rep. 2018;39:25–30. https://doi.org/10.1007/8904_2017_44.

    Article  PubMed  Google Scholar 

  75. Kölker S, Christensen E, Leonard JV, Greenberg CR, Burlina AB, Burlina AP, et al. Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I). J Inherit Metab Dis. 2007;30(1):5–22. https://doi.org/10.1007/s10545-006-0451-4.

    Article  PubMed  Google Scholar 

  76. Sauer SW, Okun JG, Fricker G, Mahringer A, Müller I, Crnic LR, et al. Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem. 2006;97(3):899–910. https://doi.org/10.1111/j.1471-4159.2006.03813.x.

    Article  PubMed  CAS  Google Scholar 

  77. Sauer SW, Opp S, Mahringer A, Kamiński MM, Thiel C, Okun JG, et al. Glutaric aciduria type I and methylmalonic aciduria: simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. Biochim Biophys Acta. 2010;1802(6):552–60. https://doi.org/10.1016/j.bbadis.2010.03.003.

    Article  PubMed  CAS  Google Scholar 

  78. Olivera-Bravo S, Ribeiro CA, Isasi E, Trías E, Leipnitz G, Díaz-Amarilla P, et al. Striatal neuronal death mediated by astrocytes from the Gcdh-/- mouse model of glutaric acidemia type I. Hum Mol Genet. 2015;24(16):4504–15. https://doi.org/10.1093/hmg/ddv175.

    Article  PubMed  CAS  Google Scholar 

  79. Strauss KA, Lazovic J, Wintermark M, Morton DH. Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency. Brain. 2007;130(Pt 7):1905–20. https://doi.org/10.1093/brain/awm058.

    Article  PubMed  Google Scholar 

  80. •• Strauss KA, Donnelly P, Wintermark M. Cerebral haemodynamics in patients with glutaryl-coenzyme A dehydrogenase deficiency. Brain. 2010;133(1):76–92. https://doi.org/10.1093/brain/awp297One of the first reports that deep into haemodynamic problems found in GA-I patients.

    Article  PubMed  Google Scholar 

  81. Zinnanti WJ, Lazovic J, Wolpert EB, Antonetti DA, Smith MB, Connor JR, et al. A diet-induced mouse model for glutaric aciduria type I. Brain. 2006;129(4):899–910. https://doi.org/10.1093/brain/awl009.

    Article  PubMed  Google Scholar 

  82. Zinnanti WJ, Lazovic J, Housman C, LaNoue K, O’Callaghan JP, Simpson I, et al. Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. J Clin Invest. 2007;117(11):3258–70. https://doi.org/10.1172/JCI31617.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Mühlhausen C, Ott N, Chalajour F, Tilki D, Freudenberg F, Shahhossini M, et al. Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I. Pediatr Res. 2006;59(2):196–202. https://doi.org/10.1203/01.pdr.0000197313.44265.cb.

    Article  PubMed  Google Scholar 

  84. Külkens S, Harting I, Sauer S, Zschocke J, Hoffmann GF, Gruber S, et al. Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency. Neurology. 2005;64(12):2142–4. https://doi.org/10.1212/01.WNL.0000167428.12417.B2.

    Article  PubMed  Google Scholar 

  85. Chugani HT, Hovda DA, Villablanca JR, Phelps ME, Xu WF. Metabolic maturation of the brain: a study of local cerebral glucose utilization in the developing cat. J Cereb Blood Flow Metab. 1991;11(1):35–47. https://doi.org/10.1038/jcbfm.1991.4.

    Article  PubMed  CAS  Google Scholar 

  86. Chugani HT, Phelps ME. Imaging human brain development with positron emission tomography. J Nucl Med. 1991;32(1):23–6.

    PubMed  CAS  Google Scholar 

  87. Olivera S, Fernandez A, Latini A, Rosillo JC, Casanova G, Wajner M, et al. Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: possible implications for GAI pathogenesis. Neurobiol Dis. 2008;32(3):528–34. https://doi.org/10.1016/j.nbd.2008.09.011.

    Article  PubMed  CAS  Google Scholar 

  88. Olivera-Bravo S, Fernández A, Sarlabós MN, Rosillo JC, Casanova G, Jiménez M, et al. Neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia-I. PLoS One. 2011;6(6):e20831. https://doi.org/10.1371/journal.pone.0020831.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Olivera-Bravo S, Isasi E, Fernández A, Rosillo JC, Jiménez M, Casanova G, et al. White matter injury induced by perinatal exposure to glutaric acid. Neurotox Res. 2014;25(4):381–91. https://doi.org/10.1007/s12640-013-9445-9.

    Article  PubMed  CAS  Google Scholar 

  90. Isasi E, Barbeito L, Olivera-Bravo S. Increased blood-brain barrier permeability and alterations in perivascular astrocytes and pericytes induced by intracisternal glutaric acid. Fluids Barriers CNS. 2014;11:15. https://doi.org/10.1186/2045-8118-11-15This paper describes neurovascular unit abnormalities and pericyte compromise in a GA-I pharmacological model.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. •• Isasi E, Korte N, Abudara V, Attwell D, Olivera-Bravo S. Glutaric acid affects pericyte contractility and migration: possible implications for GA-I pathogenesis. Mol Neurobiol. 2019;56(11):7694–707. https://doi.org/10.1007/s12035-019-1620-4This paper describes how pericytes can be affected by GA-I accumulated metabolites.

    Article  PubMed  CAS  Google Scholar 

  92. Gould IG, Tsai P, Kleinfeld D, Linninger A. The capillary bed offers the largest hemodynamic resistance to the cortical blood supply. J Cereb Blood Flow Metab. 2017;37(1):52–68. https://doi.org/10.1177/0271678X16671146.

    Article  PubMed  CAS  Google Scholar 

  93. Attwell D, Mishra A, Hall CN, O'Farrell FM. Dalkara T4. What is a pericyte? J Cereb Blood Flow Metab. 2016;36(2):451–5. https://doi.org/10.1177/0271678X15610340.

    Article  PubMed  CAS  Google Scholar 

  94. Nortley R, Korte N, Izquierdo P, Hirunpattarasilp C, Mishra A, Jaunmuktane Z, et al. Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science. 2019;365(6450):eaav9518. https://doi.org/10.1126/science.aav9518.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Mahfoud A, Domínguez CL, Rizzo C, Ribes A. In utero macrocephaly as clinical manifestation of glutaric aciduria type I. Report of a novel mutation. Rev Neurol. 2004;39(10):939–42. https://doi.org/10.33588/rn.3910.2004258.

    Article  PubMed  CAS  Google Scholar 

  96. Braissant O, Jafari P, Remacle N, Cudré-Cung HP, Do Vale Pereira S, Ballhausen D. Immunolocalization of glutaryl-CoA dehydrogenase (GCDH) in adult and embryonic rat brain and peripheral tissues. Neuroscience. 2017;343:355–63. https://doi.org/10.1016/j.neuroscience.2016.10.049.

    Article  PubMed  CAS  Google Scholar 

  97. Vanlandewijck M, He L, Mäe MA, Ando K, Del Gaudio F, Nahar K, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018;554(7693):475–80. https://doi.org/10.1038/nature25739.

    Article  PubMed  CAS  Google Scholar 

  98. Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005;97(6):512–23. https://doi.org/10.1161/01.RES.0000182903.16652.d7.

    Article  PubMed  CAS  Google Scholar 

  99. Bonkowski D, Katyshev V, Balabanov RD. The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival. Fluids Barriers CNS. 2011;8(1):8. https://doi.org/10.1186/2045-8118-8-8.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Yao Y, Chen ZL, Norris EH, Strickland S. Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun. 2014;5:3413. https://doi.org/10.1038/ncomms4413.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Gundersen GA, Vindedal GF, Skare O, Nagelhus EA. Evidence that pericytes regulate aquaporin-4 polarization in mouse cortical astrocytes. Brain Struct Funct. 2014;219(6):2181–6. https://doi.org/10.1007/s00429-013-0629-0.

    Article  PubMed  CAS  Google Scholar 

  102. Castro V, Skowronska M, Lombardi J, He J, Seth N, Velichkovska M, et al. Occludin regulates glucose uptake and ATP production in pericytes by influencing AMP-activated protein kinase activity. J Cereb Blood Flow Metab. 2018;38(2):317–32. https://doi.org/10.1177/0271678X17720816.

    Article  PubMed  CAS  Google Scholar 

  103. Nakamura K, Kamouchi M, Arimura K, Nishimura A, Kuroda J, Ishitsuka K, et al. Extracellular acidification activates cAMP responsive element binding protein via Na+/H+ exchanger isoform 1-mediated Ca2+ oscillation in central nervous system pericytes. Arterioscler Thromb Vasc Biol. 2012;32(11):2670–7. https://doi.org/10.1161/ATVBAHA.112.254946.

    Article  PubMed  CAS  Google Scholar 

  104. Hartmann DA, Underly RG, Grant RI, Watson AN, Lindner V, Shih AY. Pericyte structure and distribution in the cerebral cortex revealed by high-resolution imaging of transgenic mice. Neurophotonics. 2015;2(4):041402. https://doi.org/10.1117/1.NPh.2.4.041402.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Dias Moura Prazeres PH, Sena IFG, Borges IDT, de Azevedo PO, Andreotti JP, de Paiva AE, et al. Pericytes are heterogeneous in their origin within the same tissue. Dev Biol. 2017;427(1):6–11. https://doi.org/10.1016/j.ydbio.2017.05.001.

    Article  PubMed  CAS  Google Scholar 

  106. Yamazaki T, Mukouyama YS. Tissue specific origin, development, and pathological perspectives of pericytes. Front Cardiovasc Med. 2018;5:78. https://doi.org/10.3389/fcvm.2018.00078.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Sung JH, Hayano M, Desnick RJ. Mannosidosis: pathology of the nervous system. J Neuropathol Exp Neurol. 1977;36(5):807–20. https://doi.org/10.1097/00005072-197709000-00004.

    Article  PubMed  CAS  Google Scholar 

  108. Abbott NJ. Blood-brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis. 2013;36(3):437–49. https://doi.org/10.1007/s10545-013-9608-0.

    Article  PubMed  CAS  Google Scholar 

  109. Nepomnyashchikh GI, Soboleva MK, Aidagulova SV. Pathohistological and ultrastructural study of systemic vasculopathy (Fabry disease). Bull Exp Biol Med. 2003;135(2):202–5. https://doi.org/10.1023/a:1023896504448.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Histology and Embriology, Faculty of Medicine, University of the Republic, Gral. Flores Av., 2125, Montevideo, Uruguay

    Eugenia Isasi

  2. Cell and Molecular Neurobiology, Clemente Estable Institute (IIBCE), 3318 Italia Av., Montevideo, Uruguay

    Eugenia Isasi & Silvia Olivera-Bravo

Authors
  1. Eugenia Isasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Olivera-Bravo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Silvia Olivera-Bravo.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human Studies/Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors were performed in accordance with all applicable ethical standards including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Pericytes

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Isasi, E., Olivera-Bravo, S. Pericytes in Neurometabolic Diseases. Curr. Tissue Microenviron. Rep. 1, 131–141 (2020). https://doi.org/10.1007/s43152-020-00012-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43152-020-00012-x

Keywords

Search

Navigation