Peripheral axotomy slows motoneuron degeneration in a transgenic mouse line expressing mutant SOD1 G93A

Kong, Jiming; Xu, Zuoshang

doi:10.1002/(sici)1096-9861(19990920)412:2<373::aid-cne13>3.0.co;2-n

Cited by 32 publications

(29 citation statements)

References 44 publications

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“…Interestingly, axotomy was found to reduce the extent of motor neuron degeneration at the end stage of disease in SOD1 G93A mice (45). Because all surviving motor axons exhibited diameters smaller than 4.5 m, this led to hypothesize an apparent threshold of vulnerability correlating with axon size (45). However, this suggestion is not supported by the results presented here.…”

Section: G37rsupporting

confidence: 93%

“…These results show that reduction of axonal caliber in TH mice did not alleviate degeneration of motor neurons at risk in disease caused by mutant SOD1. Other mechanisms could then account for the increased resistance of motor axons after axotomy in SOD1 G93A mice (45). For instance, astrocytes and microglia activation in mice expressing mutant SOD1 (26)(27)(28)46) may enhance levels of cytokines in the spinal cord.…”

Section: G37rcontrasting

confidence: 57%

“…On the basis of axonal regeneration studies in mice expressing the SOD1 G93A mutant, Kong et al (45) recently suggested that there is a threshold of selective vulnerability of motor axons to degeneration at 4-5 m in caliber. Interestingly, axotomy was found to reduce the extent of motor neuron degeneration at the end stage of disease in SOD1 G93A mice (45). Because all surviving motor axons exhibited diameters smaller than 4.5 m, this led to hypothesize an apparent threshold of vulnerability correlating with axon size (45).…”

Section: G37rmentioning

confidence: 99%

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Reduction of axonal caliber does not alleviate motor neuron disease caused by mutant superoxide dismutase 1

Nguyen

Larivière

Julien

2000

Proc. Natl. Acad. Sci. U.S.A.

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It is well established that motor neurons with large axon caliber are selectively affected in amyotrophic lateral sclerosis (ALS). To investigate whether high neurofilament (NF) content and large axonal caliber are factors that predispose motor neurons to selective degeneration in ALS, we generated mice expressing a mutant form of superoxide dismutase 1 (SOD1 G37R ) linked to familial ALS in a context of one allele for each NF gene being disrupted. A Ϸ40% decrease of NF protein content detected in triple heterozygous knockout mice shifted the calibers of large axons in L5 ventral root from 5-9 m to 1-5 m, altering neither the normal subunit stoichiometry and morphological distribution of NFs nor levels of other cytoskeletal proteins. This considerable reduction in NF burden and caliber of axons did not extend the life span of SOD1 G37R mice nor did it alleviate the loss of motor axons. Moreover, increasing the density of NFs in axons by overexpressing a NF-L transgene did not accelerate disease in SOD1 G37R mice. These results do not support the current view that high NF content and large caliber of axons may account for the selective vulnerability of motor neurons in ALS caused by mutant SOD1.amyotrophic lateral sclerosis ͉ Cu͞Zn superoxide dismutase ͉ neurofilaments ͉ transgenic mice ͉ knockout mice

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Section: G37rsupporting

confidence: 93%

Section: G37rcontrasting

confidence: 57%

Section: G37rmentioning

confidence: 99%

See 1 more Smart Citation

Reduction of axonal caliber does not alleviate motor neuron disease caused by mutant superoxide dismutase 1

Nguyen

Larivière

Julien

2000

Proc. Natl. Acad. Sci. U.S.A.

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“…This result suggests that RAd injection did not accelerate motor neuron degeneration and will not interfere with our observation on the disease progression after the nerve injection. This was also consistent with our previous observation that axotomy (a more severe injury than viral injection) does not accelerate motor neuron degeneration (30) and the well-established observation that rodents tolerate the first generation RAd well.…”

Section: Nerve Injection Of Rad Caused Inflammation But Did Not Affecsupporting

confidence: 92%

Nerve Injection of Viral Vectors Efficiently Transfers Transgenes into Motor Neurons and Delivers RNAi Therapy Against ALS

Wang²,

Xia³

et al. 2009

Antioxidants & Redox Signaling

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RNA interference (RNAi) mediates sequence-specific gene silencing, which can be harnessed to silencing diseasecausing genes for therapy. Particularly suitable diseases are those caused by dominant, gain-of-function type of gene mutations. In these diseases, the mutant gene generates a mutant protein or RNA product, which possesses toxic properties that harm cells. By silencing the mutant gene, the toxicity can be lessened because the amount of the toxic product is lowered in cells. In this report, we tested RNAi therapy in a mouse model for amyotrophic lateral sclerosis (ALS), which causes motor neuron degeneration, paralysis, and death. We used a transgenic model that overexpresses mutant Cu, Zn superoxide dismutase (SOD1G93A), which causes ALS by a gained toxic property. We delivered RNAi using recombinant adenovirus (RAd) and adeno-associated virus serotype 2 (AAV2). We compared the efficiency of RNAi delivery between injecting the viral vectors into muscle and into nerve, and found that nerve injetion is more efficient in delivering RNAi to motor neurons. Based on this data, we conducted therapeutic trials in the mouse model and found that nerve injection of RAd, but not AAV2, at the disease onset had a modest therapeutic efficacy. These results highlight the potential and the challenges in delivering RNAi therapy by gene therepy. Antioxid. Redox Signal. 11, 1523Signal. 11, -1534

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“…4 Interestingly, axotomy of either the L5 ventral root or sciatic nerve in mutant SOD1-transgenic mice has been reported to actually slow the progression of disease and result in a slowing of motor neuron loss. 5 After crush injury of the sciatic nerve in which the integrity of the nerve was not compromised and regeneration was allowed to occur, it appeared that motor neuron loss was more dramatic on the side of crush injury and was accompanied by an acceleration of disease appearance. The authors speculate that the increased demands placed on regenerating motor neurons in the crush injury side may have resulted in increased metabolic demands resulting in their demise but that the lack of regenerative capacity in axotomized nerves does not place such demands on motor neurons.…”

Section: Discussionmentioning

confidence: 99%

Amyotrophic Lateral Sclerosis Presenting With a Clivus Mass and Dysarthria

Maragakis

Pardo

2006

Journal of Clinical Neuromuscular Disease

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A patient developed dysarthria and was found to have fibrous dysplasia of the clivus accompanied by cranial nerve impingement, particularly the hypoglossal canal. The dysarthria progressed to more severe bulbar dysfunction and a subsequent diagnosis of amyotrophic lateral sclerosis. This case highlights a discussion of the potential influences of focal lesions on the site of symptom onset in this neurodegenerative disease.A 41-year-old right-handed man presented with dysarthria, dysphagia, and weight loss. Examination initially showed mild tongue atrophy with fasciculations and dysarthria but no significant limb weakness or upper motor neuron findings. The patient underwent magnetic resonance imaging (MRI) of the brain that revealed a mass in the clivus with potential impingement on cranial nerves IX-XII ( Figure 1). Biopsy of this mass was consistent with fibrous dysplasia without evidence of malignancy, and resection was not performed. Over the next year, he developed slowly progressing dysarthria and dysphagia accompanied by dyspnea with mild exertion. This was followed by right upper limb weakness. He never developed diplopia, sensory symptoms, or bowel or bladder incontinence. His family history was notable for a maternal first cousin who died at 50 years of age from amyotrophic lateral sclerosis (ALS) with an initial presentation of difficulty with ambulation. Neither of the patient's parents had similar symptoms.Neurological examination 1 year after the onset of symptoms showed an intact mental status. His speech was profoundly dysarthric, but his language was fluent. Cranial nerve exam was notable for bifacial weakness. His tongue was atrophic with fasciculations bilaterally. Motor examination showed weakness of neck flexion and asymmetric weakness in the upper limbs. Specifically, MRC grade for neck flexion strength was 4; deltoids were 4+ right and 5 left; biceps were 4+ bilaterally; triceps were 4 right and 4+ left; wrist extensors were 4 bilaterally; intrinsic muscles of the hand were 5 on the right and 5 on the left; thumb flexion was 4 bilaterally; hip flexion was 5 bilaterally; leg extension was 5 bilaterally; foot dorsiflexion and plantar flexion were 5 bilaterally. Deep tendon reflexes: jaw jerk was slightly increased. Biceps reflexes were 3 bilaterally; triceps were 2 bilaterally; patellar reflexes were 3 bilaterally. He had crossed adductors. Ankle jerk reflexes were 2 bilaterally. His plantar response was flexor. He had reduced tone in the upper limbs. This was accompanied by atrophy of both upper limbs, most notably in deltoid muscles. He had fasciculations in the cervical paraspinous muscles, trapezius, multiple muscles in the arms, and the quadriceps muscles bilaterally. Sensory examination was intact. Coordination was intact to finger-nosefinger and heel-to-shin testing. He did not have a Romberg sign, and gait exam demonstrated normal toe-heel and tandem gait.Laboratory analysis consisted of a normal cerebrospinal fluid analysis. Cervical spine MRI demonstrated mild cervical spondylosis. ...

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Peripheral axotomy slows motoneuron degeneration in a transgenic mouse line expressing mutant SOD1 G93A

Cited by 32 publications

References 44 publications

Reduction of axonal caliber does not alleviate motor neuron disease caused by mutant superoxide dismutase 1

Reduction of axonal caliber does not alleviate motor neuron disease caused by mutant superoxide dismutase 1

Nerve Injection of Viral Vectors Efficiently Transfers Transgenes into Motor Neurons and Delivers RNAi Therapy Against ALS

Amyotrophic Lateral Sclerosis Presenting With a Clivus Mass and Dysarthria

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