Mice with a mutation in the dynein heavy chain 1 gene display sensory neuropathy but lack motor neuron disease

Dupuis, Luc; Fergani, Anissa; Braunstein, Kerstin E.; Eschbach, Judith; Holl, N.; Frydman, René; Aguilar, Jose Luis Gonzalez de; Zoerner, Björn; Schwalenstöcker, Birgit; Ludolph, Albert C.; Loeffler, Jean Philippe

doi:10.1016/j.expneurol.2008.09.019

Cited by 64 publications

(53 citation statements)

References 23 publications

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“…S4). Motor neuron loss was similar in this mixed background as in previous studies in the original FVB/N background [20,19]. However, Htr2b ablation in SOD1(G86R) mice triggered atrophy of motoneuron cell bodies that was not present in SOD1(G86R); Htr2b +/+ mice (Fig.…”

Section: The Lack Of 5-ht 2b Receptor Accelerates Disease Progressionsupporting

confidence: 83%

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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Section: The Lack Of 5-ht 2b Receptor Accelerates Disease Progressionsupporting

confidence: 83%

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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“…Cramping mice display early onset motor and behavioural abnormalities such as abnormal gait, hind limb clasping, motor incoordination, muscle weakness and hyperactivity. A relatively mild proprioceptive neuropathy was proved previously in dynein mutant mice (Dupuis et al, 2009;Chen et al, 2007;Ilieva et al, 2008), but this does not explain the overall behavioural disturbances observed here, rather central involvement is suggested. The phenotype of Cra/+ mice resembles striatal pathology.…”

Section: Discussioncontrasting

confidence: 85%

“…Initially it was suggested that Cra/+ and Loa/+ mice display lower motor neuron degeneration, but these findings were not reproduced. On the contrary, a proprioceptive sensory neuropathy was observed in these mice (Ilieva et al, 2008;Dupuis et al, 2009;Chen et al, 2007). However we think that this could not fully explain the mouse phenotype and aimed at a more detailed characterisation.…”

Section: I2 Axonal Transport and The Molecular Motor Dyneinmentioning

confidence: 87%

“…cDNA synthesis was performed using 1 µg of total RNA (iScript cDNA Synthesis kit; Bio-Rad, Marne La Coquette, France). PCR analysis was carried out as described (Dupuis et al, 2009) on a Bio-Rad CFX96 System using iQSYBR Green Supermix. A specific standard curve was performed for each gene in parallel, and each sample was quantified in duplicate.…”

Section: Real Time (Rt) Qpcrmentioning

confidence: 99%

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The role of axonal transport and mitochondrial dysfunction in neurodegeneration-focusing on Huntington's disease

Kisztina¹

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“…12,13 Malformations of cortical development (MCDs) were found in 10 individuals from 2 separate studies. 14,15 Three tail domain mutations in the mouse homolog of DYNC1H1 have been described: "legs at odd angles" (Loa), "crawling" (Cra1), and "sprawling" (Swl), 16,17 all sharing motor and sensory deficits and the Loa mice demonstrating cortical migration defects. 18 Phenotypic differences among these models and the emerging diversity of reported patients, suggests that the human DYNC1H1 clinical spectrum extends beyond SMA-LED.…”

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confidence: 99%

Novel mutations expand the clinical spectrum of DYNC1H1 -associated spinal muscular atrophy

et al. 2015

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Objective: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Methods:Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1.Results: We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anteriormedial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. Conclusion:Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions. Neurology ® 2015;84:668-679 GLOSSARY ADHD 5 attention deficit hyperactivity disorder; BICD2 5 bicaudal D homolog 2 (Drosophila); CBCL 5 Child Behavior Checklist; DYNC1H1 5 dynein, cytoplasmic 1, heavy chain 1; LED 5 lower extremity predominance; Loa 5 legs at odd angles; MCD 5 malformation of cortical development; SMA 5 spinal muscular atrophy.

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Mice with a mutation in the dynein heavy chain 1 gene display sensory neuropathy but lack motor neuron disease

Cited by 64 publications

References 23 publications

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

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

The role of axonal transport and mitochondrial dysfunction in neurodegeneration-focusing on Huntington's disease

Novel mutations expand the clinical spectrum of DYNC1H1 -associated spinal muscular atrophy

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