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

Abstract

Mutations in Parkinson disease (PD)3 is a major neurodegenerative disease of the adulthood affecting the extrapyramidal motor system (1). The brains of patients affected with PD are characterized by a loss of neurons in the brainstem monoaminergic neurons, e.g. dopamine neurons in the substantia nigra and noradrenergic neurons in the locus caeruleus, which is accompanied by the deposition of Lewy bodies (LBs) in the cytoplasm of remaining neurons. LBs are characteristic spherical intracytoplasmic inclusions composed of filaments of ϳ7-10 nm in diameter and are pathognomonic for PD and related dementing disorder, dementia with Lewy bodies (DLB) (2). A small percentage of patients inherit PD as an autosomal dominant trait (familial PD; FPD), and missense mutations (3-5) or multiplications (6 -8) of the ␣-synuclein gene have been identified in these families. LBs in the brains of patients with sporadic PD or DLB were shown to be composed of ␣-synuclein (9, 10). Glial cytoplasmic inclusions in the brains of patients with multiple system atrophy, another major sporadic neurodegenerative disease, or dystrophic neurites in Hallervorden-Spatz disease also were shown to be composed of ␣-synuclein, and these neurodegenerative diseases characterized by deposition of ␣-synuclein are collectively designated "synucleinopathies" (2). In vitro studies suggested that ␣-synuclein aggregates and forms filaments that are similar to those seen in PD or DLB brains, and amino acid substitutions linked to familial PD (A53T, A30P, or E46K) have been shown to enhance the aggregation of ␣-synuclein possibly through conformational changes (11-14), implicating deposition of ␣-synuclein in the pathogenesis of synucleinopathies including PD. Taken together with the gene dosage effects of ␣-synuclein in a subset of FPD (i.e. duplication and triplication), transgenic overexpression of ␣-synuclein in neurons would be a rational strategy to model neurodegeneration in PD.A number of transgenic models overexpressing ␣-synuclein using heterologous organisms Drosophila (21,22), Caenorhabditis elegans (23), yeast (24)) have been reported, and some abnormal behavioral or pathological phenotypes have been documented in a subset of these animal models. However, an ideal model in which deposition of ␣-synuclein in dopamine neurons, the most vulnerable subset of neurons in PD, causes behavioral phenotypes that are inherent to the functions of dopamine neurons, has not been established yet. Here we describe a transgenic C. elegans model in which human ␣-synuclein overexpressed specifically in dopamine neurons causes an abnormal phenotype in food-sensing behavior that has been attributed to the function of C. elegans dopamine neurons (25), in a manner dependent on FPD-linked mutations, through reduction of neuronal dopamine.

Functional Analysis of VPS41-Mediated Neuroprotection inCaenorhabditis elegansand Mammalian Models of Parkinson's Disease

“…While the precise form of ␣-syn aggregates comprising the toxic species in vivo remains unresolved, enhanced ␣-syn expression has been conclusively associated with neurotoxicity and PD (Singleton et al, 2003). In C. elegans, transgenic overexpression of ␣-syn leads to age-dependent ␣-syn accumulation and dopaminergic neuron degeneration (Lakso et al, 2003;Cao et al, 2005;Kuwahara et al, 2006;Hamamichi et al, 2008;van Ham et al, 2008;Karpinar et al, 2009). Depletion of the E1-like enzyme required for the initiation of autophagosome formation, atg-7, results in neurodegeneration in mice (Komatsu et al, 2006) as well as enhanced ␣-syn accumulation in C. elegans .…”

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

“…Expression of human α-syn under the DA transporter (dat-1) promoter results in age-and dose-dependent neurodegeneration of DA neurons (Fig. 1); α-syn-induced degeneration of neurons in C. elegans has been reported by several laboratories [14][15][16][17]. For example, when α-syn mRNA levels are expressed at lower levels in 1 transgenic line (Fig.…”

Oxidative Stress in Parkinson's Disease; Parallels Between Current Animal Models, Human Studies and Cells

“…The over-expression of -synuclein increased the loss in dopaminergic neurons in both drosophila and C. elegans models. (Feany and Bender 2000, Kuwahara et al 2006, Lakso et al 2003. However, only the dopaminergic loss in the drosophila model is progressive.…”