Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans.
Mutations in alpha-synuclein gene cause familial form of Parkinson disease, and deposition of wild-type alpha-synuclein as Lewy bodies occurs as a hallmark lesion of sporadic Parkinson disease and dementia with Lewy bodies, implicating alpha-synuclein in the pathogenesis of Parkinson disease and related neurodegenerative diseases. Dopamine neurons in substantia nigra are the major site of neurodegeneration associated with alpha-synuclein deposition in Parkinson disease. Here we establish transgenic Caenorhabditis elegans (TG worms) that overexpresses wild-type or familial Parkinson mutant human alpha-synuclein in dopamine neurons. The TG worms exhibit accumulation of alpha-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 alpha-synuclein, without overt loss of neuronal cell bodies. Notably, TG worms expressing A30P or A53T mutant alpha-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 beta-synuclein. The present TG worms exhibit dopamine neuron-specific dysfunction caused by accumulation of alpha-synuclein, which would be relevant to the genetic and compound screenings aiming at the elucidation of pathological cascade and therapeutic strategies for Parkinson disease.
Kuwahara
Tomoki
T
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo Bunkyoku Tokyo, 113-0033 Japan.
Koyama
Akihiko
A
Gengyo-Ando
Keiko
K
Masuda
Mayumi
M
Kowa
Hisatomo
H
Tsunoda
Makoto
M
Mitani
Shohei
S
Iwatsubo
Takeshi
T
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics*; D004195:Disease Models, Animal; D004298:Dopamine / Q000494:pharmacology / Q000502:physiology*; D005247:Feeding Behavior / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D009474:Neurons / Q000502:physiology; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D010641:Phenotype; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D004298:Dopamine