Neuromotor alterations and cerebellar deficits in aged arylsulfatase A-deficient transgenic mice

D’Hooge, Rudi; Hartmann, Dieter; Manil, Jacqueline; Colin, Fabienne; Gieselmann, Volkmar; Deyn, Peter Paul De

doi:10.1016/s0304-3940(99)00647-3

Cited by 54 publications

(26 citation statements)

References 17 publications

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“…38 Gait abnormalities due to cerebellar dysfunction 39 or neurodegeneration have been reported in mouse models for lysosomal storage diseases, 40,41 genes within the Down syndrome critical region, 42 genes encoding presynaptic proteins, 43 deficiency of transcription factors, 20,21 musculoskeletal disorders, 44 and polyglutamine diseases. 45 Although the number of polymorphic polyglutamine repeats in human RAI1 is implicated in modulating the onset of spinocerebellar ataxia, 46 mice carry only four glutamines in this region, and polymorphic CAG repeats have not been reported.…”

Section: Discussionmentioning

confidence: 99%

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

et al. 2008

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The retinoic acid induced 1 (RAI1) gene when deleted or mutated results in Smith-Magenis syndrome (SMS), while duplication of 17p11.2, including RAI1, results in the dup(17)(p11.2) syndrome characterized by mental retardation, growth and developmental delays, and hyperactivity. Mouse models for these human syndromes may help define critical roles for RAI1 in mammalian development and homeostasis that otherwise cannot be deduced from patient studies. A mouse model for duplication, Dp(11)17 þ , involving Rai1 has been reported. However, this mutant was engineered on a mixed genetic background confounding phenotypic effects due to possible modifier genes. We have therefore created and evaluated mice with a graded series of four (hemizygous) and six (homozygous) copies of Rai1, and overexpressing Rai1 41.5-fold and 42-fold, respectively. Data show that Rai1-transgenic mice have growth retardation, increased locomotor activity, and abnormal anxiety-related behavior compared to wild-type littermates. Rai1-transgenic mice also have an altered gait with short strides and long sways, impaired ability on a cagetop hang test, decreased forelimb grip strength, and a dominant social behavior. Further, analyses of homozygous transgenic mice revealed a dosage-dependent exacerbation of the phenotype, including extreme growth retardation, severe neurological deficits, and increased hyperactivity. Our results show that Rai1 dosage has major consequences on molecular processes involved in growth, development, and neurological and behavioral functions, thus providing evidence for several dosage-thresholds for phenotypic manifestations causing dup(17)(p11.2) syndrome or SMS in humans.

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Section: Discussionmentioning

confidence: 99%

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

et al. 2008

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“…Impaired motor coordination has been shown in aging ASA-deficient mice and related to the loss of cerebellar Purkinje cells in these animals. 2,4 Peripheral nervous system defects may also contribute, at least partially, to the neuromotor impairments in ASA knockouts, and the observed therapy-related improvement of peripheral axon diameters could possibly attenuate some of these impairments. Our behavioral observations indeed suggest marginal improvement of neurological symptoms in ASA-deficient mice.…”

Section: Figure 4 Cross-sectional Areas Of Axons Of Myelinated Fibersmentioning

confidence: 99%

“…2 The deficient mice show various progressive cerebellar deficits and a decline in brain stem auditory-evoked potentials between the age of 3 and 9 months. 4 This is due to a loss of ganglion cells in the acoustic ganglion of ASA-deficient mice. 5 Cell culture experiments indicate that the metabolic defect of cells deficient for an individual soluble lysosomal enzyme can be cross-corrected by exogenous application of this enzyme.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations

et al. 2002

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“…4 ARSA knockout mice develop a disease that resembles MLD, however, symptoms are less severe. [5][6][7] The clinical signs, which include gait disturbance, impaired motor coordination and hyperactivity, become apparent at around 1 year of age, but they do not shorten the lifespan of the mice. The fact that a milder phenotype is observed in ARSA knockout mice is probably due to the lack of significant cerebral demyelination.…”

Section: Introductionmentioning

confidence: 99%

Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer

et al. 2006

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Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by genetic deficiency of arylsulfatase A (ARSA) enzyme. Failure in catalyzing the degradation of its major substrate, sulfatide (Sulf), in oligodendrocytes and Schwann cells leads to severe demyelination in the peripheral (PNS) and central nervous system (CNS), and early death of MLD patients. The ARSA knockout mice develop a disease that resembles MLD but is milder, without significant demyelination in the PNS and CNS. We showed that adeno-associated virus serotype 5-mediated gene transfer in the brain of ARSA knockout mice reverses Sulf storage and prevents neuropathological abnormalities and neuromotor disabilities when vector injections are performed at a pre-symptomatic stage of disease. Direct injection of viral particles into the brain of ARSA knockout mice at a symptomatic stage results in sustained expression of ARSA, prevention of Sulf storage and neuropathological abnormalities. Despite these significant corrections, the treated mice continue to develop neuromotor disability. We show that more subtle biochemical abnormalities involving gangliosides and galactocerebroside are in fact not corrected.

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Neuromotor alterations and cerebellar deficits in aged arylsulfatase A-deficient transgenic mice

Cited by 54 publications

References 17 publications

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations

Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer

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