Background and gender effects on survival in the TgN(SOD1-G93A)1Gur mouse model of ALS

Heiman‐Patterson, Terry; Deitch, Jeffrey S.; Blankenhorn, Elizabeth P.; Erwin, Kirsten; Perreault, Marielle J.; Alexander, Borisov; Byers, Nathaniel; Toman, Inka; Alexander, Guillermo M.

doi:10.1016/j.jns.2005.02.006

Cited by 202 publications

(170 citation statements)

References 30 publications

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“…Sex‐specific differences in disease onset and progression as well as response to therapy have been reported in a number of studies 17, 25, 34. In the current study, we found no significant difference when we compared overall disease onset and survival between male and female α CAR IGF‐1 LV‐treated mice.…”

Section: Discussionsupporting

confidence: 46%

“…The congenic C57BL/6J Tg (SOD1 G93A)1Gur(G93A‐SOD1) mice (Jackson Laboratory, Bar Harbor, ME) were used25 and were backcrossed onto the wild‐type C57BL/6 mouse background (Charles River Laboratories, Wilmington, MA) for >10 generations. A priori power analysis revealed that 12 animals per group (both males and females) was a sufficient sample size in order to detect a medium effect with 80% power 26.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 46%

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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“…S2; 38-125 d; 8-10 axons imaged per age group). However, because of the reported longer survival of female SOD1 G93A mice (32), only female mice were used for further analyses.…”

Section: Resultsmentioning

confidence: 99%

Deficits in axonal transport precede ALS symptoms in vivo

Bilsland¹,

Sahai

Kelly

et al. 2010

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

359

343

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ALS is a fatal neurodegenerative disease characterized by selective motor neuron death resulting in muscle paralysis. Mutations in superoxide dismutase 1 (SOD1) are responsible for a subset of familial cases of ALS. Although evidence from transgenic mice expressing human mutant SOD1 G93A suggests that axonal transport defects may contribute to ALS pathogenesis, our understanding of how these relate to disease progression remains unclear. Using an in vivo assay that allows the characterization of axonal transport in single axons in the intact sciatic nerve, we have identified clear axonal transport deficits in presymptomatic mutant mice. An impairment of axonal retrograde transport may therefore represent one of the earliest axonal pathologies in SOD1 G93A mice, which worsens at an early symptomatic stage. A deficit in axonal transport may therefore be a key pathogenic event in ALS and an early disease indicator of motor neuron degeneration.

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“…Indeed, differences in genetic background have been shown to influence the survival of hemizygous SOD1 G93A transgenic mice (58,139), with a 14-28 day increase in survival on the C57BL=6 congenic, as compared to the B6SJL hybrid, background. Currently, it is hypothesized that multiple SJL-derived modifier genes act in concert with Nox2-deficiency to significantly enhance the survival of SOD1 G93A mice, and pedigree analysis of survival from the F1 and F2 generations in the Marden et al study is consistent with this hypothesis (90).…”

Section: Nadph Oxidases Influence Disease Progression In a Sod1mentioning

confidence: 99%

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Carter

Anklesaria

Choi

et al. 2009

Antioxidants & Redox Signaling

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Enhanced redox-stress caused by neuroinflammation, mitochondria, and NADPH oxidases has been hypothesized to play critical roles in disease progression of amyotrophic lateral sclerosis (ALS). However, distinguishing whether the redox-stress observed in ALS is due to a primary defect in cellular reactive oxygen species metabolism=catabolism, or is a secondary consequence of neuroinflammation, has been difficult and the issue remains a matter of debate. Emerging evidence suggests that defects in genes that regulate NADPH oxidases may account for at least some forms of ALS. NADPH oxidases are key signaling complexes that influence cellular responses to growth factors and cytokines. In this context, NADPH oxidase-derived reactive oxygen species exert spatial control over the redox-dependent activation of certain pro-inflammatory receptors. Understanding the biology of how NADPH oxidases control cell signaling may help to clarify how genetic determinants of ALS lead to dysregulated pro-inflammatory signaling. This review provides a framework for understanding endosomal signaling through NADPH oxidases and potential mechanisms whereby gene defects in various forms of ALS may influence this cellular process and lead to motor neuron degeneration. Lastly, this review discusses past and current efforts to treat ALS using antioxidant therapies, as well as the limitations and advantages of each of these approaches. Antioxid. Redox Signal. 11, 1569-1586.

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Background and gender effects on survival in the TgN(SOD1-G93A)1Gur mouse model of ALS

Cited by 202 publications

References 30 publications

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

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

Deficits in axonal transport precede ALS symptoms in vivo

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

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