Effect of transgene copy number on survival in the G93A SOD1 transgenic mouse model of ALS

Alexander, Guillermo M.; Erwin, Kirsten; Byers, Nathaniel; Deitch, Jeffrey S.; Augelli, Brian J.; Blankenhorn, Elizabeth P.; Heiman‐Patterson, Terry

doi:10.1016/j.molbrainres.2004.07.002

Cited by 146 publications

(142 citation statements)

References 18 publications

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“…As in our study, the mice with high copy number of the hSOD1 G93A transgene are known to exhibit high velocity of disease progression and short lifespan of about 130 days with the average symptomatic duration of 30 days between the onset at 14-15 weeks and clinically endpoint around 17-20 weeks [15,18,21]. On the contrary, mice with low copy numbers of the same transgene have the average lifespan of 240 days and slower progression rate with the symptomatic duration of 100 days [23]. In our study, E2 treatment extends the lifespan by 8 days in the ovariectomized mice, which approximately corresponds to 27 days in the mice with low copy numbers, suggesting its potential usage as a candidate for combined therapy.…”

Section: Discussionmentioning

confidence: 58%

Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice

Choi

Lee

Gwag

et al. 2008

Journal of the Neurological Sciences

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Section: Discussionmentioning

confidence: 58%

Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice

Choi

Lee

Gwag

et al. 2008

Journal of the Neurological Sciences

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“…For studying axon morphology and reconstructing motor units, SOD-mutant mice were crossed with Thy1-YFP 16 (Tg(Thy1-YFP)16Jrs/J) and Thy1-YFP H (Tg(Thy1-YFPH)2Jrs/J) mice, respectively (37). Genomic copy numbers of the SOD transgene were confirmed by using quantitative PCR as described (38) and yielded the following ΔCT values: SOD G85R 5.8; SOD WT 6.2; SOD G93A 7.1. All animal work conformed to institutional guidelines and was approved by the Animal Study Committee of the Regierung von Oberbayern.…”

Section: Methodsmentioning

confidence: 99%

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Marinković

Reuter

Brill

et al. 2012

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

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Axonal transport deficits have been reported in many neurodegenerative conditions and are widely assumed to be an immediate causative step of axon and synapse loss. By imaging changes in axonal morphology and organelle transport over time in several animal models of amyotrophic lateral sclerosis (ALS), we now find that deficits in axonal transport of organelles (mitochondria, endosomes) and axon degeneration can evolve independently. This conclusion rests on the following results: (i) Axons can survive despite long-lasting transport deficits: In the SOD G93A model of ALS, transport deficits are detected soon after birth, months before the onset of axon degeneration. (ii) Transport deficits are not necessary for axon degeneration: In the SOD G85R model of ALS, motor axons degenerate, but transport is unaffected. (iii) Axon transport deficits are not sufficient to cause immediate degeneration: In mice that overexpress wild-type superoxide dismutase-1 (SOD WT ), axons show chronic transport deficits, but survive. These data suggest that disturbances of organelle transport are not a necessary step in the emergence of motor neuron degeneration.

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“…Transgenic mice were genotyped according to the Jackson Laboratory protocols and were organized in subgroups of 18 (6 animals per group; (i) no treatment or mock ( α CAR eGFP LV), (ii) α CAR IGF‐1 LV, (iii) VSVG IGF‐1 LV), and they were age matched and litter matched wherever possible. Human SOD1 G93A gene copy number was assessed27 and remained stable across generations (Copy number 25+/‐ 1.2 copies hSOD1 G93A ; remained stable across mice used, F3–F6). We found only one mouse with an altered SOD1 gene copy number and this mouse was removed from the study.…”

Section: Methodsmentioning

confidence: 99%

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

Eleftheriadou

Manolaras

Irvine

et al. 2016

Ann Clin Transl Neurol

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ObjectiveWe have previously described the generation of coxsackievirus and adenovirus receptor (α CAR)‐targeted vector, and shown that intramuscular delivery in mouse leg muscles resulted in specific retrograde transduction of lumbar‐motor neurons (MNs). Here, we utilized the α CAR‐targeted vector to investigate the in vivo neuroprotective effects of lentivirally expressed IGF‐1 for inducing neuronal survival and ameliorating the neuropathology and behavioral phenotypes of the SOD1G93A mouse model of ALS.MethodsWe produced cell factories of IGF‐1 expressing lentiviral vectors (LVs) bearing α CAR or Vesicular Stomatitis Virus glycoprotein (VSV‐G) on their surface so as to compare neuroprotection from MN transduced versus muscle transduced cells. We performed intramuscular delivery of either α CAR IGF‐1 or VSVG IGF‐1 LVs into key muscles of SOD1G93A mice prior to disease onset at day 28. Motor performance, coordination and gait analysis were assessed weekly.ResultsWe observed substantial therapeutic efficacy only with the α CAR IGF‐1 LV pretreatment with up to 50% extension of survival compared to controls. α CAR IGF‐1 LV‐treated animals retained muscle tone and had better motor performance during their prolonged survival. Histological analysis of spinal cord samples at end‐stage further confirmed that α CAR IGF‐1 LV treatment delays disease onset by increasing MN survival compared with age‐matched controls. Intrastriatal injection of α CAR eGFP LV in rats leads to transduction of neurons and glia locally and neurons in olfactory bulb distally.InterpretationOur data are indicative of the efficacy of the α CAR IGF‐1 LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS.

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Effect of transgene copy number on survival in the G93A SOD1 transgenic mouse model of ALS

Cited by 146 publications

References 18 publications

Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice

Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

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