SpringerLink
Log in

Peroxisomal Dysfunction and Oxidative Stress in Neurodegenerative Disease: A Bidirectional Crosstalk

  • Chapter
  • First Online:
Peroxisome Biology: Experimental Models, Peroxisomal Disorders and Neurological Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1299))

Abstract

Peroxisomes are multifunctional organelles best known for their role in cellular lipid and hydrogen peroxide metabolism. In this chapter, we review and discuss the diverse functions of this organelle in brain physiology and neurodegeneration, with a particular focus on oxidative stress. We first briefly summarize what is known about the various nexuses among peroxisomes, the central nervous system, oxidative stress, and neurodegenerative disease. Next, we provide a comprehensive overview of the complex interplay among peroxisomes, oxidative stress, and neurodegeneration in patients suffering from primary peroxisomal disorders. Particular examples that are discussed include the prototypic Zellweger spectrum disorders and X-linked adrenoleukodystrophy, the most prevalent peroxisomal disorder. Thereafter, we elaborate on secondary peroxisome dysfunction in more common neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Finally, we highlight some issues and challenges that need to be addressed to progress towards therapies and prevention strategies preserving, normalizing, or improving peroxisome activity in patients suffering from neurodegenerative conditions.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Notes

  1. 1.

    We apologize to colleagues whose work could not be cited due to space limitations.

Abbreviations

ABCD:

ATP-binding cassette subfamily D

AD:

Alzheimer’s disease

ALDP:

Adrenoleukodystrophy protein

ALS:

Amyotrophic lateral sclerosis

CNS:

Central nervous system

DAO:

D-amino acid oxidase

DHA:

Docosahexaenoic acid

EAE:

Experimental allergic encephalomyelitis

MS:

Multiple sclerosis

PD:

Parkinson’s disease

PEX:

Peroxin

PPA:

Peroxisome-proliferating agent

PPAR:

Peroxisome proliferator-activated receptor

PUFA:

Polyunsaturated fatty acid

ROS:

Reactive oxygen species

VLCFA:

Very-long-chain fatty acid

X-ALD:

X-linked adrenoleukodystrophy

ZSD:

Zellweger spectrum disorder

References

We apologize to colleagues whose work could not be cited due to space limitations.

  1. Islinger M, Voelkl A, Fahimi HD et al (2018) The peroxisome: an update on mysteries 2.0. Histochem Cell Biol 150:443–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Van Veldhoven PP (2010) Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. J Lipid Res 51:2863–2895

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Lismont C, Revenco I, Fransen M (2019) Peroxisomal hydrogen peroxide metabolism and signaling in health and disease. Int J Mol Sci 20:E3673

    Article  PubMed  CAS  Google Scholar 

  4. Lismont C, Nordgren M, Van Veldhoven PP et al (2015) Redox interplay between mitochondria and peroxisomes. Front Cell Dev Biol 3:35

    Article  PubMed  PubMed Central  Google Scholar 

  5. Di Cara F, Andreoletti P, Trompier D et al (2019) Peroxisomes in immune response and inflammation. Int J Mol Sci 20:E3877

    Article  PubMed  CAS  Google Scholar 

  6. Fransen M, Lismont C, Walton P (2017) The peroxisome-mitochondria connection: how and why? Int J Mol Sci 18:E1126

    Article  PubMed  CAS  Google Scholar 

  7. Schönenberger MJ, Kovacs WJ (2017) Isolation of peroxisomes from mouse brain using a continuous Nycodenz gradient: a comparison to the isolation of liver and kidney peroxisomes. Methods Mol Biol 1595:13–26

    Article  PubMed  CAS  Google Scholar 

  8. Kassmann CM, Quintes S, Rietdorf J et al (2011) A role for myelin-associated peroxisomes in maintaining paranodal loops and axonal integrity. FEBS Lett 585:2205–2211

    Article  CAS  PubMed  Google Scholar 

  9. Berger J, Dorninger F, Forss-Petter S et al (2016) Peroxisomes in brain development and function. Biochim Biophys Acta 1863:934–955

    Article  CAS  PubMed  Google Scholar 

  10. Van Veldhoven PP, Baes M (2013) Peroxisome-deficient invertebrate and vertebrate animal models. Front Physiol 4:335

    PubMed  PubMed Central  Google Scholar 

  11. Cobley JN, Fiorello ML, Bailey DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15:490–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cenini G, Lloret A, Cascella R (2019) Oxidative stress in neurodegenerative diseases: from a mitochondrial point of view. Oxidative Med Cell Longev 2019:2105607

    Article  CAS  Google Scholar 

  13. Schlüter A, Real-Chicharro A, Gabaldón T et al (2010) PeroxisomeDB 2.0: an integrative view of the global peroxisomal metabolome. Nucleic Acids Res 38:D800–D805

    Article  PubMed  CAS  Google Scholar 

  14. Wanders RJA (2018) Peroxisomal disorders: improved laboratory diagnosis, new defects and the complicated route to treatment. Mol Cell Probes 40:60–69

    Article  CAS  PubMed  Google Scholar 

  15. Dorninger F, Forss-Petter S, Berger J (2017) From peroxisomal disorders to common neurodegenerative diseases - the role of ether phospholipids in the nervous system. FEBS Lett 591:2761–2788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brodde A, Teigler A, Brugger B et al (2012) Impaired neurotransmission in ether lipid-deficient nerve terminals. Hum Mol Genet 21:2713–2724

    Article  CAS  PubMed  Google Scholar 

  17. Schönfeld P, Reiser G (2016) Brain lipotoxicity of phytanic acid and very long-chain fatty acids. Harmful cellular/mitochondrial activities in Refsum disease and X-linked adrenoleukodystrophy. Aging Dis 7:136–149

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zarrouk A, Vejux A, Nury T et al (2012) Induction of mitochondrial changes associated with oxidative stress on very long chain fatty acids (C22:0, C24:0, or C26:0)-treated human neuronal cells (SK-NB-E). Oxidative Med Cell Longev 2012:623257

    Article  CAS  Google Scholar 

  19. Busanello EN, Lobato VG, Zanatta  et al (2014) Pristanic acid provokes lipid, protein, and DNA oxidative damage and reduces the antioxidant defenses in cerebellum of young rats. Cerebellum 13:751–759

    Article  CAS  PubMed  Google Scholar 

  20. Leipnitz G, Amaral AU, Fernandes CG et al (2011) Pristanic acid promotes oxidative stress in brain cortex of young rats: a possible pathophysiological mechanism for brain damage in peroxisomal disorders. Brain Res 1382:259–265

    Article  CAS  PubMed  Google Scholar 

  21. Borges CG, Canani CR, Fernandes CG et al (2015) Reactive nitrogen species mediate oxidative stress and astrogliosis provoked by in vivo administration of phytanic acid in cerebellum of adolescent rats: a potential contributing pathomechanism of cerebellar injury in peroxisomal disorders. Neuroscience 304:122–132

    Article  CAS  PubMed  Google Scholar 

  22. De Munter S, Verheijden S, Régal L et al (2015) Peroxisomal disorders: a review on cerebellar pathologies. Brain Pathol 25:663–678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. ten Brink HJ, van den Heuvel CM, Poll-The BT et al (1993) Peroxisomal disorders: concentrations of metabolites in cerebrospinal fluid compared with plasma. J Inherit Metab Dis 16:587–590

    Article  PubMed  Google Scholar 

  24. Verhoeven NM, Kulik W, van den Heuvel CM et al (1995) Pre- and postnatal diagnosis of peroxisomal disorders using stable-isotope dilution gas chromatography--mass spectrometry. J Inherit Metab Dis 18(Suppl 1):45–60

    Article  PubMed  Google Scholar 

  25. Rahim RS, Chen M, Nourse CC et al (2016) Mitochondrial changes and oxidative stress in a mouse model of Zellweger syndrome neuropathogenesis. Neuroscience 334:201–213

    Article  CAS  PubMed  Google Scholar 

  26. Ahlemeyer B, Gottwald M, Baumgart-Vogt E (2012) Deletion of a single allele of the Pex11β gene is sufficient to cause oxidative stress, delayed differentiation and neuronal death in mouse brain. Dis Model Mech 5:125–140

    Article  CAS  PubMed  Google Scholar 

  27. Bottelbergs A, Verheijden S, Van Veldhoven PP et al (2012) Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system. J Neuroinflammation 9:61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Deon M, Marchetti DP, Donida B et al (2016) Oxidative stress in patients with X-linked adrenoleukodystrophy. Cell Mol Neurobiol 36:497–512

    Article  CAS  PubMed  Google Scholar 

  29. Moser HW, Mahmood A, Raymond GV (2007) X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 3:140–151

    Article  PubMed  Google Scholar 

  30. Ranea-Robles P, Launay N, Ruiz M et al (2018) Aberrant regulation of the GSK-3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy. EMBO Mol Med 10:e8604

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Singh I, Pujol A (2010) Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis. Brain Pathol 20:838–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nury T, Zarrouk A, Ragot K et al (2017) 7-Ketocholesterol is increased in the plasma of X-ALD patients and induces peroxisomal modifications in microglial cells: potential roles of 7-ketocholesterol in the pathophysiology of X-ALD. J Steroid Biochem Mol Biol 169:123–136

    Article  CAS  PubMed  Google Scholar 

  33. Jo DS, Cho DH (2019) Peroxisomal dysfunction in neurodegenerative diseases. Arch Pharm Res 42:393–406

    Article  CAS  PubMed  Google Scholar 

  34. Lévy E, El Banna N, Baïlle D et al (2019) Causative links between protein aggregation and oxidative stress: a review. Int J Mol Sci 20:E3896

    Article  PubMed  CAS  Google Scholar 

  35. Sasabe J, Miyoshi Y, Suzuki M et al (2012) D-amino acid oxidase controls motoneuron degeneration through D-serine. Proc Natl Acad Sci U S A 109:627–632

    Article  CAS  PubMed  Google Scholar 

  36. Wojsiat J, Zoltowska KM, Laskowska-Kaszub K et al. (2018) Oxidant/antioxidant imbalance in Alzheimer’s disease: therapeutic and diagnostic prospects. Oxidative Med Cell Longev 2018:6435861

    Google Scholar 

  37. Porcellotti S, Fanelli F, Fracassi A et al (2015) Oxidative stress during the progression of β-amyloid pathology in the neocortex of the Tg2576 mouse model of Alzheimer’s disease. Oxidative Med Cell Longev 2015:967203

    Article  Google Scholar 

  38. Kou J, Kovacs GG, Höftberger R et al (2011) Peroxisomal alterations in Alzheimer’s disease. Acta Neuropathol 122:271–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Igarashi M, Ma K, Gao F et al (2011) Disturbed choline plasmalogen and phospholipid fatty acid concentrations in Alzheimer’s disease prefrontal cortex. J Alzheimers Dis 24:507–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shi Y, Sun X, Sun Y et al (2016) Elevation of cortical C26:0 due to the decline of peroxisomal β-oxidation potentiates amyloid β generation and spatial memory deficits via oxidative stress in diabetic rats. Neuroscience 315:125–135

    Article  CAS  PubMed  Google Scholar 

  41. Inestrosa NC, Carvajal FJ, Zolezzi JM et al (2013) Peroxisome proliferators reduce spatial memory impairment, synaptic failure, and neurodegeneration in brains of a double transgenic mice model of Alzheimer’s disease. J Alzheimers Dis 33:941–959

    Article  CAS  PubMed  Google Scholar 

  42. Nell HJ, Au JL, Giordano CR et al (2016) Targeted antioxidant, catalase-SKL, reduces beta-amyloid toxicity in the rat brain. Brain Pathol 27:86–94

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Bose A, Beal MF (2019) Mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell models of Parkinson’s disease. Eur J Neurosci 49:525–532

    Article  PubMed  Google Scholar 

  44. Marin R, Fabelo N, Martín V et al (2017) Anomalies occurring in lipid profiles and protein distribution in frontal cortex lipid rafts in dementia with Lewy bodies disclose neurochemical traits partially shared by Alzheimer’s and Parkinson’s diseases. Neurobiol Aging 49:52–59

    Article  CAS  PubMed  Google Scholar 

  45. Suzuki K, Iseki E, Togo T et al (2007) Neuronal and glial accumulation of alpha- and beta-synucleins in human lipidoses. Acta Neuropathol 114:481–489

    Article  CAS  PubMed  Google Scholar 

  46. Yakunin E, Moser A, Loeb V et al (2010) Alpha-synuclein abnormalities in mouse models of peroxisome biogenesis disorders. J Neurosci Res 88:866–876

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Yakunin E, Loeb V, Kisos H et al (2012) Α-synuclein neuropathology is controlled by nuclear hormone receptors and enhanced by docosahexaenoic acid in a mouse model for Parkinson’s disease. Brain Pathol 22:280–294

    Article  CAS  PubMed  Google Scholar 

  48. Yakunin E, Kisos H, Kulik W et al (2014) The regulation of catalase activity by PPAR γ is affected by α-synuclein. Ann Clin Transl Neurol 1:145–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rane P, Sarmah D, Bhute S et al (2019) Novel targets for Parkinson’s disease: addressing different therapeutic paradigms and conundrums. ACS Chem Neurosci 10:44–57

    Article  CAS  PubMed  Google Scholar 

  50. Miville-Godbout E, Bourque M, Morissette M et al (2016) Plasmalogen augmentation reverses striatal dopamine loss in MPTP mice. PLoS One 11:e0151020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Faissner S, Plemel JR, Gold R et al (2019) Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat Rev Drug Discov 18:905–922

    Google Scholar 

  52. Gray E, Rice C, Hares K et al (2014) Reductions in neuronal peroxisomes in multiple sclerosis grey matter. Mult Scler 20:651–659

    Article  PubMed  Google Scholar 

  53. Singh I, Paintlia AS, Khan M et al (2004) Impaired peroxisomal function in the central nervous system with inflammatory disease of experimental autoimmune encephalomyelitis animals and protection by lovastatin treatment. Brain Res 1022:1–11

    Article  CAS  PubMed  Google Scholar 

  54. Singh I, Samuvel DJ, Choi S et al (2018) Combination therapy of lovastatin and AMP-activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model. Immunology 154:434–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Szalardy L, Zadori D, Bencsik K et al (2017) Unlike PPARgamma, neither other PPARs nor PGC-1alpha is elevated in the cerebrospinal fluid of patients with multiple sclerosis. Neurosci Lett 651:128–133

    Article  CAS  PubMed  Google Scholar 

  56. Gonzalo H, Brieva L, Tatzber F et al (2012) Lipidome analysis in multiple sclerosis reveals protein lipoxidative damage as a potential pathogenic mechanism. J Neurochem 123:622–634

    Article  CAS  PubMed  Google Scholar 

  57. Hossain MS, Abe Y, Ali F et al (2017) Reduction of ether-type glycerophospholipids, plasmalogens, by NF-κB signal leading to microglial activation. J Neurosci 37:4074–4092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Young JM, Nelson JW, Cheng J et al (2015) Peroxisomal biogenesis in ischemic brain. Antioxid Redox Signal 22:109–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Moruno-Manchon JF, Uzor NE, Kesler SR et al (2018) Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy. Mol Cell Neurosci 86:65–71

    Article  CAS  PubMed  Google Scholar 

  60. Debbabi M, Nury T, Zarrouk A et al (2016) Protective effects of α-tocopherol, γ-tocopherol and oleic acid, three compounds of olive oils, and no effect of Trolox, on 7-ketocholesterol-induced mitochondrial and peroxisomal dysfunction in microglial BV-2 cells. Int J Mol Sci 17:E1973

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the KU Leuven (C14/18/088), the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (Onderzoeksprojecten G095315N, G091819N, and GOA8619N), the ERA-Net for Research Programmes on Rare Diseases (PERescue), and H2020-MSCA-ITN (812968). CL is supported by a postdoctoral fellowship of the Research Foundation—Flanders (1213620 N).

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Laboratory of Lipid Biochemistry and Protein Interactions, KU Leuven, Leuven, Belgium

    Marc Fransen, Iulia Revenco, Hongli Li, Cláudio F. Costa, Celien Lismont & Paul P. Van Veldhoven

Authors
  1. Marc Fransen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iulia Revenco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongli Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cláudio F. Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Celien Lismont
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul P. Van Veldhoven
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marc Fransen .

Editor information

Editors and Affiliations

  1. Team ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ EA 7270/University of Bourgogne Franche-Comté/Inserm, Dijon, France

    Gérard Lizard

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Fransen, M., Revenco, I., Li, H., Costa, C.F., Lismont, C., Van Veldhoven, P.P. (2020). Peroxisomal Dysfunction and Oxidative Stress in Neurodegenerative Disease: A Bidirectional Crosstalk. In: Lizard, G. (eds) Peroxisome Biology: Experimental Models, Peroxisomal Disorders and Neurological Diseases. Advances in Experimental Medicine and Biology, vol 1299. Springer, Cham. https://doi.org/10.1007/978-3-030-60204-8_2

Download citation

Publish with us

Policies and ethics

Search

Navigation