Alpha-Synuclein Abnormalities in Mouse Models of Peroxisome Biogenesis Disorders

Overview

Journal J Neurosci Res

Specialty Neurology

Date 2009 Oct 16

PMID 19830841

Citations 21

Authors

Eugenia Yakunin

Ann Moser

Virginie Loeb

Ann Saada

Phyllis Faust

Denis I Crane

Myriam Baes

Ronit Sharon

Affiliations

Soon will be listed here.

Abstract

alpha-Synuclein (alphaS) is a presynaptic protein implicated in Parkinson's disease (PD). Growing evidence implicates mitochondrial dysfunction, oxidative stress, and alphaS-lipid interactions in the gradual accumulation of alphaS in pathogenic forms and its deposition in Lewy bodies, the pathological hallmark of PD and related synucleinopathies. The peroxisomal biogenesis disorders (PBD), with Zellweger syndrome serving as the prototype of this group, are characterized by malformed and functionally impaired peroxisomes. Here we utilized the PBD mouse models Pex2-/-, Pex5-/-, and Pex13-/- to study the potential effects of peroxisomal dysfunction on alphaS-related pathogenesis. We found increased alphaS oligomerization and phosphorylation and its increased deposition in cytoplasmic inclusions in these PBD mouse models. Furthermore, we show that alphaS abnormalities correlate with the altered lipid metabolism and, specifically, with accumulation of long chain, n-6 polyunsaturated fatty acids that occurs in the PBD models.

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References

Poulos A, Sharp P, Johnson D, Easton C . The occurrence of polyenoic very long chain fatty acids with greater than 32 carbon atoms in molecular species of phosphatidylcholine in normal and peroxisome-deficient (Zellweger's syndrome) brain. Biochem J. 1988; 253(3):645-50. PMC: 1149355. DOI: 10.1042/bj2530645. View

Hardy J, Cai H, Cookson M, Gwinn-Hardy K, Singleton A . Genetics of Parkinson's disease and parkinsonism. Ann Neurol. 2006; 60(4):389-98. DOI: 10.1002/ana.21022. View

Manning-Bog A, McCormack A, Li J, Uversky V, Fink A, Di Monte D . The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem. 2001; 277(3):1641-4. DOI: 10.1074/jbc.C100560200. View

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

Spillantini M, Schmidt M, Lee V, Trojanowski J, Jakes R, Goedert M . Alpha-synuclein in Lewy bodies. Nature. 1997; 388(6645):839-40. DOI: 10.1038/42166. View

Sharon R, Bar-Joseph I, Mirick G, Serhan C, Selkoe D . Altered fatty acid composition of dopaminergic neurons expressing alpha-synuclein and human brains with alpha-synucleinopathies. J Biol Chem. 2003; 278(50):49874-81. DOI: 10.1074/jbc.M309127200. View

Robinson B, Johnson D, Poulos A . Metabolism of hexacosatetraenoic acid (C26:4,n-6) in immature rat brain. Biochem J. 1990; 267(2):561-4. PMC: 1131329. DOI: 10.1042/bj2670561. View

Dirkx R, Vanhorebeek I, Martens K, Schad A, Grabenbauer M, Fahimi D . Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities. Hepatology. 2005; 41(4):868-78. DOI: 10.1002/hep.20628. View

Lee V, Trojanowski J . Mechanisms of Parkinson's disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron. 2006; 52(1):33-8. DOI: 10.1016/j.neuron.2006.09.026. View

10.

Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg M . alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002; 4(2):160-4. DOI: 10.1038/ncb748. View

11.

Halliwell B . Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging. 2001; 18(9):685-716. DOI: 10.2165/00002512-200118090-00004. View

12.

Devi L, Raghavendran V, Prabhu B, Avadhani N, Anandatheerthavarada H . Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem. 2008; 283(14):9089-100. PMC: 2431021. DOI: 10.1074/jbc.M710012200. View

13.

Lopez-Huertas E, Charlton W, Johnson B, Graham I, Baker A . Stress induces peroxisome biogenesis genes. EMBO J. 2000; 19(24):6770-7. PMC: 305880. DOI: 10.1093/emboj/19.24.6770. View

14.

Liu Y, Bjorkman J, Urquhart A, Wanders R, Crane D, Gould S . PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis disorders. Am J Hum Genet. 1999; 65(3):621-34. PMC: 1377968. DOI: 10.1086/302534. View

15.

Maxwell M, Bjorkman J, Nguyen T, Sharp P, Finnie J, Paterson C . Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype. Mol Cell Biol. 2003; 23(16):5947-57. PMC: 166343. DOI: 10.1128/MCB.23.16.5947-5957.2003. View

16.

Baes M, Van Veldhoven P . Generalised and conditional inactivation of Pex genes in mice. Biochim Biophys Acta. 2006; 1763(12):1785-93. DOI: 10.1016/j.bbamcr.2006.08.018. View

17.

Altschuler Y, Barbas S, Terlecky L, Tang K, Hardy S, Mostov K . Redundant and distinct functions for dynamin-1 and dynamin-2 isoforms. J Cell Biol. 1998; 143(7):1871-81. PMC: 2175237. DOI: 10.1083/jcb.143.7.1871. View

18.

Kahle P, Neumann M, Ozmen L, Muller V, Odoy S, Okamoto N . Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol. 2001; 159(6):2215-25. PMC: 1850592. DOI: 10.1016/s0002-9440(10)63072-6. View

19.

Janssen A, Baes M, Gressens P, Mannaerts G, Declercq P, Van Veldhoven P . Docosahexaenoic acid deficit is not a major pathogenic factor in peroxisome-deficient mice. Lab Invest. 2000; 80(1):31-5. DOI: 10.1038/labinvest.3780005. View

20.

Martinez M . Polyunsaturated fatty acids in the developing human brain, erythrocytes and plasma in peroxisomal disease: therapeutic implications. J Inherit Metab Dis. 1995; 18 Suppl 1:61-75. DOI: 10.1007/BF00711429. View