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1.
Artigo em Inglês | MEDLINE | ID: mdl-25008789

RESUMO

Amyotrophic lateral sclerosis is a late-onset degenerative disease affecting motor neurons in the spinal cord, brainstem, and motor cortex. There is great variation in the expression of ALS symptoms even between siblings who both carry the same Cu/Zn superoxide dismutase (SOD1) mutations. One important use of transgenic mouse models of SOD1-ALS is the study of genetic influences on ALS severity. We utilized multiple inbred mouse strains containing the SOD1-G93A transgene to demonstrate a major quantitative trait locus (QTL) on mouse chromosome 17 resulting in a significant shift in lifespan. Reciprocal crosses between long- and short-lived strains identified critical regions, and we have narrowed the area for potential genetic modifier(s) to < 2Mb of the genome. Results showed that resequencing of this region resulted in 28 candidate genes with potentially functional differences between strains. In conclusion, these studies provide the first major modifier locus affecting lifespan in this model of FALS and, once identified, these candidate modifier genes may provide insight into modifiers of human disease and, most importantly, define new targets for the development of therapies.


Assuntos
Esclerose Lateral Amiotrófica/genética , Cromossomos Humanos Par 17/genética , Longevidade/genética , Locos de Características Quantitativas/genética , Superóxido Dismutase/genética , Esclerose Lateral Amiotrófica/mortalidade , Animais , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Eutanásia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Atividade Motora/genética , Análise de Sobrevida
2.
PLoS One ; 9(6): e99879, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24945277

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor neuron. While most cases of ALS are sporadic, 10% are familial (FALS) with 20% of FALS caused by a mutation in the gene that codes for the enzyme Cu/Zn superoxide dismutase (SOD1). There is variability in sporadic ALS as well as FALS where even within the same family some siblings with the same mutation do not manifest disease. A transgenic (Tg) mouse model of FALS containing 25 copies of the mutant human SOD1 gene demonstrates motor neuron pathology and progressive weakness similar to ALS patients, leading to death at approximately 130 days. The onset of symptoms and survival of these transgenic mice are directly related to the number of copies of the mutant gene. We report the phenotype of a very low expressing (VLE) G93A SOD1 Tg carrying only 4 copies of the mutant G93ASOD1 gene. While weakness can start at 9 months, only 74% of mice 18 months or older demonstrate disease. The VLE mice show decreased motor neurons compared to wild-type mice as well as increased cytoplasmic translocation of TDP-43. In contrast to the standard G93A SOD1 Tg mouse which always develops motor weakness leading to death, not all VLE animals manifested clinical disease or shortened life span. In fact, approximately 20% of mice older than 24 months had no motor symptoms and only 18% of VLE mice older than 22 months reached end stage. Given the variable penetrance of clinical phenotype, prolonged survival, and protracted loss of motor neurons the VLE mouse provides a new tool that closely mimics human ALS. This tool will allow the study of pathologic events over time as well as the study of genetic and environmental modifiers that may not be causative, but can exacerbate or accelerate motor neuron disease.


Assuntos
Envelhecimento/genética , Esclerose Lateral Amiotrófica/genética , Proteínas de Ligação a DNA/metabolismo , Mutação , Fenótipo , Superóxido Dismutase/genética , Envelhecimento/patologia , Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Dosagem de Genes , Expressão Gênica , Humanos , Longevidade , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/enzimologia , Neurônios Motores/patologia , Transporte Proteico , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Análise de Sobrevida
3.
Amyotroph Lateral Scler ; 12(2): 79-86, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21241159

RESUMO

Transgenic (Tg) mouse models of FALS containing mutant human SOD1 genes (G37R, G85R, D90A, or G93A missense mutations or truncated SOD1) exhibit progressive neurodegeneration of the motor system that bears a striking resemblance to ALS, both clinically and pathologically. The most utilized and best characterized Tg mice are the G93A mutant hSOD1 (Tg(hSOD1-G93A)1GUR mice), abbreviated G93A. In this review we highlight what is known about background-dependent differences in disease phenotype in transgenic mice that carry mutated human or mouse SOD1. Expression of G93A-hSOD1Tg in congenic lines with ALR, NOD.Rag1KO, SJL or C3H backgrounds show a more severe phenotype than in the mixed (B6xSJL) hSOD1Tg mice, whereas a milder phenotype is observed in B6, B10, BALB/c and DBA inbred lines. We hypothesize that the background differences are due to disease-modifying genes. Identification of modifier genes can highlight intracellular pathways already suspected to be involved in motor neuron degeneration; it may also point to new pathways and processes that have not yet been considered. Most importantly, identified modifier genes provide new targets for the development of therapies.


Assuntos
Esclerose Lateral Amiotrófica/genética , Genótipo , Camundongos Transgênicos , Fenótipo , Superóxido Dismutase/genética , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Humanos , Masculino , Camundongos , Degeneração Neural/genética , Degeneração Neural/patologia , Isoformas de Proteínas/genética , Superóxido Dismutase-1 , Taxa de Sobrevida
4.
Exp Neurol ; 214(2): 341-346, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18848933

RESUMO

The potential of MUNE as a unique electrophysiological tool to detect early motor unit abnormalities during a clinically silent period was investigated in the plasma membrane calcium ATPase 2 (PMCA2)-heterozygous mice. There was a significant reduction in MUNE in the PMCA2-heterozygous mice as compared to the wild type littermates at two months of age. In contrast, the compound motor action potential (CMAP) was not altered. The conduction velocity (CV) of the sensory nerve and sensory nerve action potentials (SNAP) were not modified indicating lack of major sensory deficits. Interestingly, despite a decline in MUNE at this age, no changes were detected in choline acetyl transferase (ChAT) positive motor neuron number in the ventral horn of the lumbar spinal cord. Hindlimb grip strength, a test that evaluates clinical dysfunction, was also similar to that of the wild type controls. However, motor neuron number significantly decreased by five months suggesting that a drop in MUNE preceded motor neuron loss. In the two-month-old PMCA2-null mice, reduced MUNE measurements coincided with lower motor neuron number and decreased hindlimb grip strength. The fall in motor neuron number was already detectable at three weeks, the earliest time studied, and became more pronounced by five months. Our results show that even partial reductions in PMCA2 levels are sufficient to cause delayed death of motor neurons and that MUNE may be a reliable and sensitive approach to detect pathology prior to cell loss and in the absence of overt clinical signs.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Degeneração Neural/patologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Potenciais de Ação/fisiologia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Sinalização do Cálcio/fisiologia , Modelos Animais de Doenças , Força da Mão , Heterozigoto , Camundongos , Camundongos Mutantes , Degeneração Neural/metabolismo , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Medula Espinal/patologia
5.
Brain Res Mol Brain Res ; 130(1-2): 7-15, 2004 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-15519671

RESUMO

Transgenic mice expressing multiple copies of the G93A mutant form of SOD1 develop motor neuron pathology and clinical symptoms similar to those seen in patients with amyotrophic lateral sclerosis (ALS). The phenotype of these mice is dependent on the number of transgene copies in their genome. Changes in transgene copy number, although rare, can sometimes occur while mating due to intra locus recombination events during meiosis. The objective of this study was to develop a real time quantitative PCR method to determine changes in transgene copy number in these mice and to evaluate the effect of transgene copy number on the phenotype of the G93A SOD1 mouse model of ALS.


Assuntos
Esclerose Lateral Amiotrófica/genética , Modelos Animais de Doenças , Dosagem de Genes , Superóxido Dismutase/genética , Transgenes/fisiologia , Animais , Humanos , Interleucina-2/genética , Interleucina-2/metabolismo , Camundongos , Camundongos Transgênicos , Fenótipo , RNA Mensageiro/metabolismo , Recombinação Genética/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Superóxido Dismutase/metabolismo , Sobrevida/fisiologia
6.
J Neurol Sci ; 193(2): 117-26, 2002 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-11790392

RESUMO

A decrease in expression of the glutamate transporter GLT-1 is thought to be responsible for the increase in extracellular glutamate observed in patients with amyotrophic lateral sclerosis (ALS) and in a transgenic mouse model of ALS. We examined protein levels of the glutamate transporters GLT-1, GLAST and EAAC1 in the G93A (SOD1) transgenic mouse model of ALS. GLT-1 was detected in two bands (72 and 150 kD). Semi-quantitative analysis of Western blots showed that GLT-1 levels in sensorimotor cortex, brain stem, and cervical and lumbar spinal cord of G93A mice did not differ significantly from controls, either at end stage or at 60- or 90-days old. Nevertheless, other differences were found in GLT-1 at end stage. The percentage of total GLT-1 in the 150 kD band increased significantly (p<0.05) in the spinal cord and was elevated in the brain stem and cortex. Furthermore, brain stem and spinal cord GLT-1 from G93A mice showed retarded mobility on gels compared to controls (M(r) approximately equal to 77.3+/-2.3 and 164.3+/-3.1 vs. 72.2+/-2.4 and 153.6+/-4.7, respectively). GLAST and EAAC1 were unchanged in both amount and mobility. These results show that a loss of GLT-1 protein is not necessary for ALS-like neurodegeneration in G93A mice. However, the changes in GLT-1 mobility and distribution indicate that GLT-1 is altered in mice with the SOD1 mutation.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Sistema Nervoso Central/metabolismo , Transportador 2 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Mutação/genética , Superóxido Dismutase/genética , Simportadores , Envelhecimento/genética , Envelhecimento/metabolismo , Sistema X-AG de Transporte de Aminoácidos/genética , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Dimerização , Modelos Animais de Doenças , Eletroforese em Gel de Poliacrilamida/métodos , Transportador 1 de Aminoácido Excitatório , Transportador 3 de Aminoácido Excitatório , Feminino , Proteínas de Transporte de Glutamato da Membrana Plasmática , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Peso Molecular , Neurônios Motores/patologia , Debilidade Muscular/genética , Debilidade Muscular/patologia , Fenótipo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1
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