Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: A window of opportunity in the search for genetic modifiers

Heiman‐Patterson, Terry; Sher, Roger B.; Blankenhorn, Elizabeth; Alexander, Guillermo M.; Deitch, Jeffrey S.; Kunst, Catherine B.; Maragakis, Nicholas J.; Cox, Gregory A.

doi:10.3109/17482968.2010.550626

Cited by 101 publications

(74 citation statements)

References 54 publications

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“…The double transgenic mice are on a C57BL6 background and this genetic background is associated with longer survival and milder disease phenotype [44][45][46], which is opposite from what we observed in double transgenic mice. Therefore, our results strongly suggest that H63D HFE is a contributing factor in ALS disease pathogenesis.…”

Section: Discussioncontrasting

confidence: 84%

“…Genetic background can influence disease onset, severity, and survival in ALS rodent models independent of transgene copy numbers [44][45][46]. The double transgenic mice are on a C57BL6 background and this genetic background is associated with longer survival and milder disease phenotype [44][45][46], which is opposite from what we observed in double transgenic mice.…”

Section: Discussioncontrasting

confidence: 83%

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H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Nandar

Neely

Simmons

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Keywords:H63D HFE SOD1(G93A) ALS Iron Oxidative stress Gliosis H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90 days (presymptomatic), 110 days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90 days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L-ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110 days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions.

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Section: Discussioncontrasting

confidence: 84%

Section: Discussioncontrasting

confidence: 83%

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Nandar

Neely

Simmons

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…2c, the mixed background increased overall survival of SOD1(G86R) mice and increased heterogeneity in survival. This effect of mixed genetic background has been previously reported, including by us [35,28]. Accelerated death of mutant SOD1 mice ablated of Htr2b was due to accelerated neurodegeneration, and not to potential confounding effects on cardiac patho-physiology.…”

Section: Discussionmentioning

confidence: 70%

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

et al. 2016

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Abstract:Microglia are the resident phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to overall increased phagocytic activity and production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in monocytes and microglia are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT 2B ), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT 2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT 2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT 2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT 2B mRNA in spinal cord and displayed less pronounced degeneration of mononuclear phagocytes than patients carrying two copies of the more common A allele. Thus functional 5-HT 2B receptors limit degeneration of spinal cord macrophages (most likely microglia), and slow disease progression in ALS. Targeting this receptor might be therapeutically useful.

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“…Mice with different genetic background to the SOD1 mutation have a different clinical course of disease, with SJL/J mice that are very susceptible to autoimmune disease having a shorter survival than mice with the BL6 background [112] and mice with ALR, NOD.Rag1KO and C3H background also showing a more severe phenotype than BL6, B10, BALB/c and DBA strains [113]. This has implications.…”

Section: Experimental Studies In Animal Modelsmentioning

confidence: 93%

The Role of Immune and Inflammatory Mechanisms in ALS

McCombe¹,

Henderson²

2011

CMM

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Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease. The cause is unknown, but genetic abnormalities have been identified in subjects with familial ALS and also in subjects with sporadic ALS. Environmental factors such as occupational exposure have been shown to be risk factors for the development of ALS. Patients differ in their clinical features and differ in the clinical course of disease. Immune abnormalities have been found in the central nervous system by pathological studies and also in the blood and CSF of subjects with ALS. Inflammation and immune abnormalities are also found in animals with a model of ALS due to mutations in the SOD1 gene. Previously it has been considered that immune abnormalities might contribute to the pathogenesis of disease. However more recently it has become apparent that an immune response can occur as a response to damage to the nervous system and this can be protective.

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Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: A window of opportunity in the search for genetic modifiers

Cited by 101 publications

References 54 publications

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

The Role of Immune and Inflammatory Mechanisms in ALS

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