Familial Parkinson Mutant α-Synuclein Causes Dopamine Neuron Dysfunction in Transgenic Caenorhabditis elegans*

Mutations in α-synuclein gene cause familial form of Parkinson disease, and deposition of wild-type α-synuclein as Lewy bodies occurs as a hallmark lesion of sporadic Parkinson disease and dementia with Lewy bodies, implicating α-synuclein in the pathogenesis of Parkinson disease and related neurodegenerative diseases. Dopamine neurons in substantia nigra are the major site of neurodegeneration associated with α-synuclein deposition in Parkinson disease. Here we establish transgenic Caenorhabditis elegans (TG worms) that overexpresses wild-type or familial Parkinson mutant human α-synuclein in dopamine neurons. The TG worms exhibit accumulation of α-synuclein in the cell bodies and neurites of dopamine neurons, and EGFP labeling of dendrites is often diminished in TG worms expressing familial Parkinson disease-linked A30P or A53T mutant α-synuclein, without overt loss of neuronal cell bodies. Notably, TG worms expressing A30P or A53T mutant α-synuclein show failure in modulation of locomotory rate in response to food, which has been attributed to the function of dopamine neurons. This behavioral abnormality was accompanied by a reduction in neuronal dopamine content and was treatable by administration of dopamine. These phenotypes were not seen upon expression of β-synuclein. The present TG worms exhibit dopamine neuron-specific dysfunction caused by accumulation of α-synuclein, which would be relevant to the genetic and compound screenings aiming at the elucidation of pathological cascade and therapeutic strategies for Parkinson disease.

[1]  S. Brenner.  The genetics of Caenorhabditis elegans. , 1974, Genetics.

[2]  J. Sulston,et al.  Dopaminergic neurons in the nematode Caenorhabditis elegans , 1975, The Journal of comparative neurology.

[3]  V. Ambros,et al.  Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. , 1991, The EMBO journal.

[4]  S. Mitani.  Genetic regulation of mec‐3 gene expression implicated in the specification of the mechanosensory neuron cell types in Caenorhabditis elegans , 1995, Development, growth & differentiation.

[5]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[6]  M. L. Schmidt,et al.  α-Synuclein in Lewy bodies , 1997, Nature.

[7]  Olaf Riess,et al.  AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease , 1998, Nature Genetics.

[8]  J Q Trojanowski,et al.  Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. , 1998, The American journal of pathology.

[9]  T. Santa,et al.  Simultaneous automatic determination of catecholamines and their 3-O-methyl metabolites in rat plasma by high-performance liquid chromatography using peroxyoxalate chemiluminescence reaction. , 1999, Analytical biochemistry.

[10]  P. Lansbury,et al.  Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Christian Haass,et al.  Subcellular Localization of Wild-Type and Parkinson's Disease-Associated Mutant α-Synuclein in Human and Transgenic Mouse Brain , 2000, The Journal of Neuroscience.

[12]  Rajesh Ranganathan,et al.  C. elegans Locomotory Rate Is Modulated by the Environment through a Dopaminergic Pathway and by Experience through a Serotonergic Pathway , 2000, Neuron.

[13]  L. Mucke,et al.  Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. , 2000, Science.

[14]  W. Bender,et al.  A Drosophila model of Parkinson's disease , 2000, Nature.

[15]  John Q. Trojanowski,et al.  Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease , 2001, Science.

[16]  V. Uversky,et al.  Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. , 2001, Biochemistry.

[17]  M. Farrer,et al.  Lack of Nigral Pathology in Transgenic Mice Expressing Human α-Synuclein Driven by the Tyrosine Hydroxylase Promoter , 2001, Neurobiology of Disease.

[18]  Peter T. Lansbury,et al.  Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct , 2001, Science.

[19]  P. Auluck,et al.  Pharmacological prevention of Parkinson disease in Drosophila , 2002, Nature Medicine.

[20]  David H. Hall,et al.  Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Trojanowski,et al.  Neuronal α-Synucleinopathy with Severe Movement Disorder in Mice Expressing A53T Human α-Synuclein , 2002, Neuron.

[22]  E. Masliah,et al.  α-Synuclein is phosphorylated in synucleinopathy lesions , 2002, Nature Cell Biology.

[23]  Hideo Fujiwara,et al.  Hyperphosphorylation and insolubility of α‐synuclein in transgenic mouse oligodendrocytes , 2002 .

[24]  Nancy A. Jenkins,et al.  Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  David W. Miller,et al.  Motor dysfunction and gliosis with preserved dopaminergic markers in human α-synuclein A30P transgenic mice , 2003, Neurobiology of Aging.

[26]  T. Dawson,et al.  Molecular Pathways of Neurodegeneration in Parkinson's Disease , 2003, Science.

[27]  J. Trojanowski,et al.  Parkinson's Disease and Related α‐Synucleinopathies Are Brain Amyloidoses , 2003, Annals of the New York Academy of Sciences.

[28]  S. Lindquist,et al.  Yeast Cells Provide Insight into Alpha-Synuclein Biology and Pathobiology , 2003, Science.

[29]  R. Blakely,et al.  Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human α‐synuclein , 2003, Journal of neurochemistry.

[30]  Janel O. Johnson,et al.  α-Synuclein Locus Triplication Causes Parkinson's Disease , 2003, Science.

[31]  J. Hoenicka,et al.  The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia , 2004, Annals of neurology.

[32]  Philippe Amouyel,et al.  α-synuclein locus duplication as a cause of familial Parkinson's disease , 2004, The Lancet.

[33]  Michel Goedert,et al.  Mutation E46K increases phospholipid binding and assembly into filaments of human α‐synuclein , 2004 .

[34]  S. Tsuji,et al.  Mostly separate distributions of CLAC- versus Abeta40- or thioflavin S-reactivities in senile plaques reveal two distinct subpopulations of beta-amyloid deposits. , 2004, The American journal of pathology.

[35]  A Dürr,et al.  Causal relation between α-synuclein locus duplication as a cause of familial Parkinson's disease , 2004, The Lancet.

[36]  M. Feany,et al.  α-Synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease , 2005, Nature Neuroscience.

[37]  Paul H. Axelsen,et al.  The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation* , 2005, Journal of Biological Chemistry.

[38]  P. Auluck,et al.  Mechanisms of Suppression of α-Synuclein Neurotoxicity by Geldanamycin in Drosophila* , 2005, Journal of Biological Chemistry.

[39]  C. Ross,et al.  α-Synuclein Phosphorylation Enhances Eosinophilic Cytoplasmic Inclusion Formation in SH-SY5Y Cells , 2005, The Journal of Neuroscience.