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Mottled Mice and Non-Mammalian Models of Menkes Disease.

ABSTRACT: Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. The ATP7A protein is a copper (Cu)-transporting ATPase expressed in all tissues and plays a critical role in the maintenance of copper homeostasis in cells of the whole body. ATP7A participates in copper absorption in the small intestine and in copper transport to the central nervous system (CNS) across the blood-brain-barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Cu is essential for synaptogenesis and axonal development. In cells, ATP7A participates in the incorporation of copper into Cu-dependent enzymes during the course of its maturation in the secretory pathway. There is a high degree of homology (>80%) between the human ATP7A and murine Atp7a genes. Mice with mutations in the Atp7a gene, called mottled mutants, are well-established and excellent models of Menkes disease. Mottled mutants closely recapitulate the Menkes phenotype and are invaluable for studying Cu-metabolism. They provide useful models for exploring and testing new forms of therapy in Menkes disease. Recently, non-mammalian models of Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals.

SUBMITTER: Lenartowicz M

PROVIDER: S-EPMC4684000 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Mottled Mice and Non-Mammalian Models of Menkes Disease.

Lenartowicz Małgorzata M Krzeptowski Wojciech W Lipiński Paweł P Grzmil Paweł P Starzyński Rafał R Pierzchała Olga O Møller Lisbeth Birk LB

Frontiers in molecular neuroscience 20151218

Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. The ATP7A protein is a copper (Cu)-transporting ATPase expressed in all tissues and plays a critical role in the maintenance of copper homeostasis in cells of the whole body. ATP7A participates in copper absorption in the small intestine and in copper transport to the central nervous system (CNS) acro ...[more]

PMID: 26732058

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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.Author summaryThis study sought to probe the normal function(s) of a protein associated with Parkinson's disease, the second most common neurodegenerative disease in humans. We used a genetic modifier approach to uncover aspects of normal protein function, via mutagenesis of mice and screening for neurological problems that are decreased or enhanced in mice that are null for α-synuclein ( Snca) . Through these studies, we identified the X-linked gene that is mutated in Menkes disease in humans as a modifier of the null Snca phenotype, specifically in female mice. The gene mutated in Menkes disease, ATP7a , encodes a copper transporter that is known to act in the trans-Golgi sub-cellular compartment. Genetic modifier effects suggest that Snca may also play a role in that compartment, potentially in the mammalian brain.

Dataset Information

Mottled Mice and Non-Mammalian Models of Menkes Disease.

Publications

Mottled Mice and Non-Mammalian Models of Menkes Disease.

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