Compensatory mechanism of motor defect in SOD1 transgenic mice by overactivation of striatal cholinergic neurons

Azzouz, Mimoun; Krężel, Wojciech; Dollé, Pascal; Vodouhe, C.; Jm, Warter; Poindron, Philippe; Borg, Jacques

doi:10.1097/00001756-199904060-00022

Cited by 11 publications

(7 citation statements)

References 8 publications

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“…7 B–I , one-way ANOVA with post hoc Tukey’s multiple-comparison test). One of the major characteristics of the hSOD1 G93A mice is the loss of SMN with age (Gurney et al, 1994; Azzouz et al, 1999). To investigate whether SMN of hSOD1 G93A -UeGFP mice undergo similar progressive cellular degeneration, we analyzed co-localization of ChAT and eGFP expression in both lumbar and cervical spinal cords of WT-UeGFP and hSOD1 G93A -UeGFP mice at different ages (P30, P60, P90, and P120).…”

Section: Resultsmentioning

confidence: 99%

eGFP Expression underUCHL1Promoter Genetically Labels Corticospinal Motor Neurons and a Subpopulation of Degeneration-Resistant Spinal Motor Neurons in an ALS Mouse Model

Yasvoina¹,

Genç²,

Jara³

et al. 2013

J. Neurosci.

126

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Understanding mechanisms that lead to selective motor neuron degeneration requires visualization and cellular identification of vulnerable neurons. Here we report generation and characterization of UCHL1-eGFP and hSOD1 G93A-UeGFP mice, novel reporter lines for cortical and spinal motor neurons. Corticospinal motor neurons (CSMN) and a subset of spinal motor neurons (SMN) are genetically labeled in UCHL1-eGFP mice, which express eGFP under the UCHL1 promoter. eGFP expression is stable and continues through P800 in vivo. Retrograde labeling, molecular marker expression, electrophysiological analysis, and cortical circuit mapping confirmed CSMN identity of eGFP+ neurons in the motor cortex. Anatomy, molecular marker expression, and electrophysiological analysis revealed that the eGFP expression is restricted to a subset of small-size SMN that are slow-twitch α and γ motor neurons. Crossbreeding of UCHL1-eGFP and hSOD1 G93A lines generated hSOD1 G93A-UeGFP mice, which displayed the disease phenotype observed in a hSOD1 G93A mouse model of ALS. eGFP+ SMN showed resistance to degeneration in hSOD1 G93A-UeGFP mice, and their slow-twitch α and γ motor neuron identity was confirmed. In contrast, eGFP+ neurons in the motor cortex of hSOD1 G93A-UeGFP mice recapitulated previously reported progressive CSMN loss and apical dendrite degeneration. Our findings using these two novel reporter lines revealed accumulation of autophagosomes along the apical dendrites of vulnerable CSMN at P60, early symptomatic stage, suggesting autophagy as a potential intrinsic mechanism for CSMN apical dendrite degeneration.

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Section: Resultsmentioning

confidence: 99%

eGFP Expression underUCHL1Promoter Genetically Labels Corticospinal Motor Neurons and a Subpopulation of Degeneration-Resistant Spinal Motor Neurons in an ALS Mouse Model

Yasvoina¹,

Genç²,

Jara³

et al. 2013

J. Neurosci.

126

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“…The loss of motoneurons shown in this model has been attributed to a dominant gain of function of this mutated SOD1 (Gurney et al, 1994;Brown, 1995). Moreover, these mice showed dopaminergic neuron degeneration in substantia nigra and overactivation of striatal cholinergic neurons (Kostic et al, 1997;Azzouz et al, 1999). The viability of cultured neural cell lines or a yeast expressing mutant SOD1 was increased by copper chelators (Rabizadeh et al, 1995;Wiedau-Pazos et al, 1996), suggesting that copper may be involved in the death of these cells.…”

mentioning

confidence: 82%

Prevention of mutant SOD1 motoneuron degeneration by copper chelatorsin vitro

et al. 2000

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“…This is surprising given the overwhelming biological evidence showing early motor system dysfunction occurring well before the onset of clinical symptoms (Wong et al, 1995; Mourelatos et al, 1996; Kennel et al, 1996; Frey et al, 2000; Shefner et al, 2001; Amendola et al, 2004; Fischer et al, 2004; Kirkinezos et al, 2005; Browne et al, 2006; Durand et al, 2006; Gould et al, 2006; Hegedus et al, 2007; Niessen et al, 2007). One possibility for the delayed clinical phenotype may be over-activation of striatal cholinergic neurons (Azzouz et al, 1999). Another possibility is axon regeneration, a phenomena that has been reported following partial muscle denervation such that axonal sprouting from nearby intact motor neurons can go on to form new synaptic connections with denervated muscle fibers (Son and Thompson 1995a, 1995b; Kang and Tian et al, 2003; Love et al,.…”

mentioning

confidence: 99%

Pre-symptomatic detection of chronic motor deficits and genotype prediction in congenic B6.SOD1G93A ALS mouse model

Hayworth

González-Lima

2009

Neuroscience

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Amyotrophic lateral sclerosis (ALS) is an incurable progressive paralytic motor neuron disease with limited therapeutic options. Since their creation by Gurney et al. (1994), transgenic SOD1G93A mice have become the benchmark pre-clinical model for screening ALS therapies. Surprisingly, despite physiological, anatomical, ultrastructural and biochemical evidence of early motor system dysfunction it has proven difficult to detect motor performance deficits in pre-symptomatic SOD1G93A mice. As an alternative to conventional forced motor tests, we investigated the progression of motor performance deficits in freely behaving pre-symptomatic congenic B6.SOD1G93A mice. We found that motor performance deficits began several weeks prior to the onset of overt clinical symptoms (postnatal day 45). More importantly, once motor performance deficits manifested, they persisted in parallel with disease progression. In addition, two physical measures of muscle girth revealed progressive hindlimb muscle atrophy that predicted genotype in individual pre-symptomatic mice with 80% accuracy. Together, these data suggest that muscle girth is a reliable and indirect measure of hindlimb muscle denervation and an early, objective marker for disease onset in congenic B6.SOD1G93A ALS mice. Moreover, we present regression equations based on hindlimb muscle girth for predicting genotype in future studies using B6.SOD1G93A mice. These findings support new objective criteria for clinical disease onset and provide objective measures that require little expertise. These studies demonstrate a cost-effective approach for more thorough evaluation of neuroprotective strategies that seek to disrupt disease mechanisms early in the disease process. To our knowledge, these findings are the first to report early chronic motor performance and physical deficits that are coincident with the earliest known motor dysfunction in any ALS mouse model.

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Compensatory mechanism of motor defect in SOD1 transgenic mice by overactivation of striatal cholinergic neurons

Cited by 11 publications

References 8 publications

eGFP Expression underUCHL1Promoter Genetically Labels Corticospinal Motor Neurons and a Subpopulation of Degeneration-Resistant Spinal Motor Neurons in an ALS Mouse Model

eGFP Expression underUCHL1Promoter Genetically Labels Corticospinal Motor Neurons and a Subpopulation of Degeneration-Resistant Spinal Motor Neurons in an ALS Mouse Model

Prevention of mutant SOD1 motoneuron degeneration by copper chelatorsin vitro

Pre-symptomatic detection of chronic motor deficits and genotype prediction in congenic B6.SOD1G93A ALS mouse model

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