Resistance of Alpha -synuclein Null Mice to the Parkinsonian Neurotoxin MPTP

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2002 Oct 12

PMID 12376616

Citations 238

Authors

William Dauer

Nikolai Kholodilov

Miquel Vila

Anne-Cecile Trillat

Rose Goodchild

Kristin E Larsen

Roland Staal

Kim Tieu

Yvonne Schmitz

Chao Annie Yuan

Marcelo Rocha

Vernice Jackson-Lewis

Steven Hersch

David Sulzer

Serge Przedborski

Robert Burke

Rene Hen

Affiliations

Soon will be listed here.

Abstract

Parkinson's disease (PD) is most commonly a sporadic illness, and is characterized by degeneration of substantia nigra dopamine (DA) neurons and abnormal cytoplasmic aggregates of alpha-synuclein. Rarely, PD may be caused by missense mutations in alpha-synuclein. MPTP, a neurotoxin that inhibits mitochondrial complex I, is a prototype for an environmental cause of PD because it produces a pattern of DA neurodegeneration that closely resembles the neuropathology of PD. Here we show that alpha-synuclein null mice display striking resistance to MPTP-induced degeneration of DA neurons and DA release, and this resistance appears to result from an inability of the toxin to inhibit complex I. Contrary to predictions from in vitro data, this resistance is not due to abnormalities of the DA transporter, which appears to function normally in alpha-synuclein null mice. Our results suggest that some genetic and environmental factors that increase susceptibility to PD may interact with a common molecular pathway, and represent the first demonstration that normal alpha-synuclein function may be important to DA neuron viability.

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References

Reinhard Jr J, Diliberto Jr E, Viveros O, Daniels A . Subcellular compartmentalization of 1-methyl-4-phenylpyridinium with catecholamines in adrenal medullary chromaffin vesicles may explain the lack of toxicity to adrenal chromaffin cells. Proc Natl Acad Sci U S A. 1987; 84(22):8160-4. PMC: 299498. DOI: 10.1073/pnas.84.22.8160. View

Nicklas W, Youngster S, Kindt M, Heikkila R . MPTP, MPP+ and mitochondrial function. Life Sci. 1987; 40(8):721-9. DOI: 10.1016/0024-3205(87)90299-2. View

Tatton N, Kish S . In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience. 1997; 77(4):1037-48. DOI: 10.1016/s0306-4522(96)00545-3. View

Conway K, Rochet J, Bieganski R, Lansbury Jr P . Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science. 2001; 294(5545):1346-9. DOI: 10.1126/science.1063522. View

Lakso M, Sauer B, Mosinger Jr B, Lee E, Manning R, Yu S . Targeted oncogene activation by site-specific recombination in transgenic mice. Proc Natl Acad Sci U S A. 1992; 89(14):6232-6. PMC: 49474. DOI: 10.1073/pnas.89.14.6232. View

Ferger B, Eberhardt O, Teismann P, De Groote C, Schulz J . Malonate-induced generation of reactive oxygen species in rat striatum depends on dopamine release but not on NMDA receptor activation. J Neurochem. 1999; 73(3):1329-32. DOI: 10.1046/j.1471-4159.1999.0731329.x. View

Lee F, Liu F, Pristupa Z, Niznik H . Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. FASEB J. 2001; 15(6):916-26. DOI: 10.1096/fj.00-0334com. View

Burrows K, Nixdorf W, Yamamoto B . Central administration of methamphetamine synergizes with metabolic inhibition to deplete striatal monoamines. J Pharmacol Exp Ther. 2000; 292(3):853-60. View

Nakao N, Nakai K, Itakura T . Metabolic inhibition enhances selective toxicity of L-DOPA toward mesencephalic dopamine neurons in vitro. Brain Res. 1998; 777(1-2):202-9. DOI: 10.1016/s0006-8993(97)01116-5. View

10.

Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho W, Castillo P . Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000; 25(1):239-52. DOI: 10.1016/s0896-6273(00)80886-7. View

11.

Scott W, Nance M, Watts R, Hubble J, Koller W, Lyons K . Complete genomic screen in Parkinson disease: evidence for multiple genes. JAMA. 2001; 286(18):2239-44. DOI: 10.1001/jama.286.18.2239. View

12.

Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S . Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet. 1998; 18(2):106-8. DOI: 10.1038/ng0298-106. View

13.

Chung K, Zhang Y, Lim K, Tanaka Y, Huang H, Gao J . Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med. 2001; 7(10):1144-50. DOI: 10.1038/nm1001-1144. View

14.

Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A . Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science. 2000; 287(5456):1265-9. DOI: 10.1126/science.287.5456.1265. View

15.

Tatton W, Kwan M, Verrier M, Seniuk N, Theriault E . MPTP produces reversible disappearance of tyrosine hydroxylase-containing retinal amacrine cells. Brain Res. 1990; 527(1):21-31. DOI: 10.1016/0006-8993(90)91056-m. View

16.

Murphy D, Rueter S, Trojanowski J, Lee V . Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 2000; 20(9):3214-20. PMC: 6773130. View

17.

Trillat A, Malagie I, Scearce K, Pons D, Anmella M, Jacquot C . Regulation of serotonin release in the frontal cortex and ventral hippocampus of homozygous mice lacking 5-HT1B receptors: in vivo microdialysis studies. J Neurochem. 1998; 69(5):2019-25. DOI: 10.1046/j.1471-4159.1997.69052019.x. View

18.

Polymeropoulos M, Lavedan C, Leroy E, Ide S, Dehejia A, Dutra A . Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997; 276(5321):2045-7. DOI: 10.1126/science.276.5321.2045. View

19.

Martin E, Scott W, Nance M, Watts R, Hubble J, Koller W . Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease. JAMA. 2001; 286(18):2245-50. PMC: 3973175. DOI: 10.1001/jama.286.18.2245. View

20.

Shimura H, Schlossmacher M, Hattori N, Frosch M, Trockenbacher A, Schneider R . Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science. 2001; 293(5528):263-9. DOI: 10.1126/science.1060627. View