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Transglutaminase 2 exacerbates ?-synuclein toxicity in mice and yeast.

ABSTRACT: ?-Synuclein is a key pathogenic protein that aggregates in hallmark lesions in Parkinson's disease and other ?-synucleinopathies. Prior in vitro studies demonstrated that it is a substrate for cross-linking by transglutaminase 2 (TG2) into higher-order species. Here we investigated whether this increased aggregation occurs in vivo and whether TG2 exacerbates ?-synuclein toxicity in Mus musculus and Saccharomyces cerevisiae. Compared with ?-synuclein transgenic (Syn(Tg)) mice, animals double transgenic for human ?-synuclein and TG2 (TG2(Tg)/Syn(Tg)) manifested greater high-molecular-weight insoluble species of ?-synuclein in brain lysates and developed ?-synuclein aggregates in the synaptic vesicle fraction. In addition, larger proteinase K-resistant aggregates developed, along with increased thioflavin-S-positive amyloid fibrils. This correlated with an exaggerated neuroinflammatory response, as seen with more astrocytes and microglia. Further neuronal damage was suggested by greater morphological disruption of nerve fibers and a trend toward decreased c-Fos immunoreactive neurons. Finally, the performance of TG2(Tg)/Syn(Tg) animals on motor behavioral tasks was worse relative to Syn(Tg) mice. Greater toxicity of ?-synuclein was also demonstrated in yeast cells coexpressing TG2. Our findings demonstrate that TG2 promotes the aggregation of ?-synuclein in vivo and that this is associated with aggravated toxicity of ?-synuclein and its downstream neuropathologic consequences.

SUBMITTER: Grosso H

PROVIDER: S-EPMC4202112 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Transglutaminase 2 exacerbates α-synuclein toxicity in mice and yeast.

Grosso Hilary H Woo Jong-Min JM Lee Kang-Woo KW Im Joo-Young JY Masliah Eliezer E Junn Eunsung E Mouradian M Maral MM

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20140626 10

α-Synuclein is a key pathogenic protein that aggregates in hallmark lesions in Parkinson's disease and other α-synucleinopathies. Prior in vitro studies demonstrated that it is a substrate for cross-linking by transglutaminase 2 (TG2) into higher-order species. Here we investigated whether this increased aggregation occurs in vivo and whether TG2 exacerbates α-synuclein toxicity in Mus musculus and Saccharomyces cerevisiae. Compared with α-synuclein transgenic (Syn(Tg)) mice, animals double tran ...[more]

PMID: 24970392

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Project description:Genetic modifier screens provide a useful tool, in diverse organisms from Drosophila to C. elegans and mice, for recovering new genes of interest that may reduce or enhance a phenotype of interest. This study reports a modifier screen, based on N-ethyl-N-nitrosourea (ENU) mutagenesis and outcrossing, designed to increase understanding of the normal function of murine α-synuclein (Snca). Human SNCA was the first gene linked to familial Parkinson's disease. Since the discovery of the genetic link of SNCA to Parkinson's nearly three decades ago, numerous studies have investigated the normal function of SNCA protein with divergent roles associated with different cellular compartments. Understanding of the normal function of murine Snca is complicated by the fact that mice with homozygous null mutations live a normal lifespan and have only subtle synaptic deficits. Here, we report that the first genetic modifier (a sensitized mutation) that was identified in our screen was the X-linked gene, ATPase copper transporting alpha (Atp7a). In humans, mutations in Atp7a are linked to to Menkes disease, a disease with pleiotropic phenotypes that include a severe neurological component. Atp7a encodes a trans-Golgi copper transporter that supplies the copper co-factor to enzymes that pass through the ER-Golgi network. Male mice that carry a mutation in Atp7a die within 3 weeks of age regardless of Snca genotype. In contrast, here we show that Snca disruption modifies the phenotype of Atp7a in female mice. Female mice that carry the Atp7a mutation, on an Snca null background, die earlier (prior to 35 days) at a significantly higher rate than those that carry the Atp7a mutation on a wildtype Snca background ATPase copper transporting alpha. Thus, Snca null mutations sensitize female mice to mutations in Atp7a, suggesting that Snca protein may have a protective effect in females, perhaps in neurons, given the co-expression patterns. Although data has suggested diverse functions for human and mouse α-synuclein proteins in multiple cell compartments, this is the first demonstration via use of genetic screening to demonstrate that Snca protein may function in the ER-Golgi system in the mammalian brain in a sex-dependent manner.

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Transglutaminase 2 exacerbates ?-synuclein toxicity in mice and yeast.

Publications

Transglutaminase 2 exacerbates α-synuclein toxicity in mice and yeast.

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