Synaptic dysfunction in disease and following injury in the developing and adult nervous system: Caveats in the choice of therapeutic intervention☆

Gould, Thomas W.; Oppenheim, Ronald W.

doi:10.1016/j.neubiorev.2007.04.015

Cited by 13 publications

(17 citation statements)

References 204 publications

(192 reference statements)

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“…These observations are consistent with the report of spontaneous Wallerian-like degeneration of the neurites of cultured sympathetic ganglia neurons that occurs in a dying-back proximal-distal pattern following knock-down of Nmnat2 [8]. Thus, endogenous Nmnat2 may play a critical role in the stabilization (maintenance) of peripheral axons and the prevention of axonal regression [1], [29], [30].…”

Section: Discussionsupporting

confidence: 91%

Nicotinamide Mononucleotide Adenylyltransferase 2 (Nmnat2) Regulates Axon Integrity in the Mouse Embryo

et al. 2012

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Using transposon-mediated gene-trap mutagenesis, we have generated a novel mouse mutant termed Blad (Bloated Bladder). Homozygous mutant mice die perinatally showing a greatly distended bladder, underdeveloped diaphragm and a reduction in total skeletal muscle mass. Wild type and heterozygote mice appear normal. Using PCR, we identified a transposon insertion site in the first intron of Nmnat2 (Nicotinamide mononucleotide adenyltransferase 2). Nmnat2 is expressed predominantly in the brain and nervous system and has been linked to the survival of axons. Expression of this gene is undetectable in Nmnat2blad/blad mutants. Examination of the brains of E18.5 Nmnat2blad/blad mutant embryos did not reveal any obvious morphological changes. In contrast, E18.5 Nmnat2blad/blad homozygotes showed an approximate 60% reduction of spinal motoneurons in the lumbar region and a more than 80% reduction in the sensory neurons of the dorsal root ganglion (DRG). In addition, facial motoneuron numbers were severely reduced, and there was virtually a complete absence of axons in the hind limb. Our observations suggest that during embryogenesis, Nmnat2 plays an important role in axonal growth or maintenance. It appears that in the absence of Nmnat2, major target organs and tissues (e.g., muscle) are not functionally innervated resulting in perinatal lethality. In addition, neither Nmnat1 nor 3 can compensate for the loss of Nmnat2. Whilst there have been recent suggestions that Nmnat2 may be an endogenous modulator of axon integrity, this work represents the first in vivo study demonstrating that Nmnat2 is involved in axon development or survival in a mammal.

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Section: Discussionsupporting

confidence: 91%

Nicotinamide Mononucleotide Adenylyltransferase 2 (Nmnat2) Regulates Axon Integrity in the Mouse Embryo

et al. 2012

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“…Recent evidence derived from the study of animal models of various neuropathological conditions has revealed that damage to axons and synapses often long precedes the activation of death pathways and the onset of clinical (i.e., functional) pathology (Raff et al 2002; Medana and Esiri 2003; Palop et al 2006; Gould and Oppenheim 2007). In the case of mouse models of ALS, muscle denervation occurs months before MN death or disease onset (Frey et al 2000; Fischer et al 2004; Gould et al 2006; Pun et al 2006).…”

Section: Literature Reviewmentioning

confidence: 99%

“…The impairment of axonal transport in SOD1 mice has been attributed to appearance of neurofilament (NF) inclusions in mutant axons (Zhang et al 1997), but mutations in transport proteins in the dynein/dynactin complex also occur (LaMonte et al 2002; Hafezparast et al 2003; Puls et al 2003). The enrichment within neurons of mitochondria near sites of activity such as axons, dendrites, and presynaptic terminals indicates that mitochondrial localization may be the target of disease toxicity in fALS as well as in other neurodegenerative diseases involving distal-to-proximal axonal pathology (Gould and Oppenheim 2007). It is an attractive possibility that altered transport of either normal or defective mitochondria to and/or from MN presynaptic terminals contributes to neuromuscular denervation and MN disease (but see, Marinkovic et al 2012).…”

Section: Literature Reviewmentioning

confidence: 99%

“…Furthermore, pathological events such as fragmentation of the Golgi apparatus, vacuolization of mitochondria, deficits in axonal transport and endoplasmic reticulum (ER) stress are observed at early postnatal ages (Mourelatos et al 1996; Stieber et al 1998; Bendotti et al 2001; Gonatas et al 2006; Saxena et al 2009). In many animal models of neuropathological conditions including ALS, there is increasing evidence that damage to axons and synapses often long precedes the activation of death pathways and the onset of clinical (i.e., functional) pathology (Coleman and Perry 2002; Raff et al 2002; Medana and Esiri 2003; Palop et al 2006; Gould and Oppenheim 2007; Saxena and Caroni 2007). …”

Section: Introductionmentioning

confidence: 99%

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Characterization of early pathogenesis in the SOD1^G93A mouse model of ALS: part I, background and methods

et al. 2013

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Charcot first described amyotrophic lateral sclerosis (ALS) in 1869; however, its causes remain largely unknown and effective, long-term treatment strategies are not available. The first mouse model of ALS was developed after the identification of mutations in the superoxide dismutase 1 (SOD1) gene in 1993, and accordingly most of our knowledge of the etiology and pathogenesis of the disease comes from studies carried out using this animal model. Although numerous preclinical trials have been conducted in the mutant SOD1 mouse models, the results have been disappointing because they did not positively translate to clinical trials. One explanation may be that current understanding of when and where pathogenesis begins is insufficient to accurately guide preclinical trials. Further characterization of these early events may provide insight into disease onset, help in the discovery of presymptomatic diagnostic disease markers, and identify novel therapeutic targets. Here, we describe the rationale, approach, and methods for our extensive analysis of early changes that included an ultrastructural examination of central and peripheral components of the neuromuscular system in the SOD1G93A mouse and correlated these alterations with early muscle denervation, motor dysfunction, and motoneuron death. We also provide a discussion of published work to review what is known regarding early pathology in the SOD1 mouse model of ALS. The significance of this work is that we have examined early pathology simultaneously in both the spinal cord and peripheral neuromuscular system, and the results are presented in the companion paper (Part II, Results and Discussion). Our results provide evidence as to why a thorough characterization of animal models throughout the life span is critical for a strong foundation to design preclinical trials that may produce meaningful results.

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“…Thus, it may be speculated that the exposure of classical MHC class I molecules loaded with "self" or "non-self" peptides on peripheral motor axons may induce an immune response with adverse effects on motoneurons. This, in turn, is of interest in relation to the emerging focus on axonal and synaptic pathology as early signs and even as key triggering factors for the onset of neurodegenerative disease (Raff et al, 2002;Selkoe, 2002;Conforti et al, 2007;Gould and Oppenheim, 2007;Saxena and Caroni, 2007). In this context, it is of interest that MHC class I mRNA has been detected in all peripheral motoneuron groups, except for the ocular motor nuclei, which are known to be spared in the motoneuron neurodegenerative disorder amyotrophic lateral sclerosis (Lindå et al, 1999).…”

Section: Mhc Class Ia Proteins and Nmj Plasticitymentioning

confidence: 99%

Classical Major Histocompatibility Complex Class I Molecules in Motoneurons: New Actors at the Neuromuscular Junction

Thams

Brodin²,

Plantman³

et al. 2009

J. Neurosci.

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Synaptic dysfunction in disease and following injury in the developing and adult nervous system: Caveats in the choice of therapeutic intervention☆

Cited by 13 publications

References 204 publications

Nicotinamide Mononucleotide Adenylyltransferase 2 (Nmnat2) Regulates Axon Integrity in the Mouse Embryo

Nicotinamide Mononucleotide Adenylyltransferase 2 (Nmnat2) Regulates Axon Integrity in the Mouse Embryo

Characterization of early pathogenesis in the SOD1^G93A mouse model of ALS: part I, background and methods

Classical Major Histocompatibility Complex Class I Molecules in Motoneurons: New Actors at the Neuromuscular Junction

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Synaptic dysfunction in disease and following injury in the developing and adult nervous system: Caveats in the choice of therapeutic intervention☆

Cited by 13 publications

References 204 publications

Nicotinamide Mononucleotide Adenylyltransferase 2 (Nmnat2) Regulates Axon Integrity in the Mouse Embryo

Nicotinamide Mononucleotide Adenylyltransferase 2 (Nmnat2) Regulates Axon Integrity in the Mouse Embryo

Characterization of early pathogenesis in the SOD1G93A mouse model of ALS: part I, background and methods

Classical Major Histocompatibility Complex Class I Molecules in Motoneurons: New Actors at the Neuromuscular Junction

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Characterization of early pathogenesis in the SOD1^G93A mouse model of ALS: part I, background and methods