Implementation of a manual for working with wobbler mice and criteria for discontinuation of the experiment

Ott, Bastian; Dahlke, Carolin; Meller, Karl; Napirei, Markus; Schmitt-John, Thomas; Brand‐Saberi, Beate; Theiß, Carsten; Saberi, Darius

doi:10.1016/j.aanat.2015.03.007

Cited by 19 publications

(28 citation statements)

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“…The wobbler mouse was first described by Falconer ( 1956 ) and has recently been reviewed (Moser et al, 2013 ; Ott et al, 2015 ) as animal model for amyotrophic lateral sclerosis (ALS; Figure 1A ). The spontaneous, recessive wobbler mutation ( wr ) was mapped to the proximal mouse chromosome 11 (Kaupmann et al, 1992 ) and the critical region was refined to a region homologous to human chromosome 2p13 (Korthaus et al, 1997 ; Resch et al, 1998 ; Fuchs et al, 2002 ).…”

Section: Vps54 and The Wobbler Phenotypementioning

confidence: 99%

VPS54 and the wobbler mouse

Schmitt-John

2015

Front. Neurosci.

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The wobbler mouse is an animal model for human motor neuron disease, such as amyotrophic lateral sclerosis (ALS). The spontaneous, recessive wobbler mutation causes degeneration of upper and lower motor neurons leading to progressive muscle weakness with striking similarities to the ALS pathology. The wobbler mutation is a point mutation affecting Vps54, a component of the Golgi-associated retrograde protein (GARP) complex. The GARP complex is a ubiquitously expressed Golgi-localized vesicle tethering complex, tethering endosome-derived vesicles to the trans Golgi network. The wobbler point mutation leads to a destabilization of the Vps54 protein and thereby the whole GARP complex. This effectuates impairments of the retrograde vesicle transport, mis-sorting of Golgi- and endosome localized proteins and on the long run defects in Golgi morphology and function. It is currently largely unknown how the destabilization of the GARP complex interferes with the pathological hallmarks, reported for the wobbler motor neuron degeneration, like neurofilament aggregation, axonal transport defects, hyperexcitability, mitochondrial dysfunction, and how these finally lead to motor neuron death. However, the impairments of the retrograde vesicle transport and the Golgi-function appear to be critical phenomena in the molecular pathology of the wobbler motor neuron disease.

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Section: Vps54 and The Wobbler Phenotypementioning

confidence: 99%

VPS54 and the wobbler mouse

Schmitt-John

2015

Front. Neurosci.

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“…Further transmission electron microscopic (TEM) analysis of DRG neurons additionally revealed high numbers of enlarged vesicles at p40 ( Figure 1D; n=5 mice, with every wobbler mouse showing these alterations in DRG neurons). This accumulation is also described in degenerating αMN of wobbler mice, typically sparing the axon hillock [12,17]. Together with the APP/Rab7 positive vesicles, this is as a hint for an impaired vesicle trafficking in DRG neurons.…”

Section: The Wobbler Defect In Drg Neuronsmentioning

confidence: 93%

“…Breeding and genotyping was done as described earlier in Ott et al [17]. For all experiments, we used heterozygous (wr/wr) asymptomatic wobbler mice from the pre-symptomatic phase at the age of postnatal day (p) 20 and symptomatic wobbler mice from the evolutionary phase at the age of p40 and age matched controls (wt/wt) from both sexes.…”

Section: Methodsmentioning

confidence: 99%

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Morphological Studies of Wobbler Mouse Dorsal Root Ganglia Show Neurofilamental Disorders

Ott¹,

Dahlke²,

Saberi³

et al. 2017

J Neurol Exp Neurosci

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with three described forms: The abundant, sporadic ALS (sALS) with approximately 90% of cases, the familial ALS (fALS) with 5-10%, and the very rare juvenile ALS (jALS) group, which is statistically less relevant. The wobbler mouse, a model for sALS, has been in the focus of research for many decades. Due to symptoms strongly resembling the human ALS pathology, the α-motor neurons (αMN) have received the most attention. With regard to pathological cellular processes, particularly those of impaired axonal transport, neuronal tissues in general should be examined. Dorsal root ganglia (DRG) cells are equipped with extremely long axons. Thus, we expected them to be an excellent target for analyzing the cellular mechanisms underlying the disease. In this study, an analysis of the distribution of heavy neurofilaments (NfH) in the perikarya and peripheral nerves of dorsal root ganglia cells from wobbler mice was performed. Here, we demonstrate that sensory neurons are also affected in wobbler mice during the progression of the disease, showing signs of degeneration like those described in the αMN. Furthermore, a highly impaired distribution of neurofilaments and a high number of phosphorylated heavy neurofilaments (pNfH) were observed, not only in large light neurons (LLN), but also in the small dark neurons (SDN) of wobbler mouse DRGs. The accumulation of pNfH in DRG as well as the loss of NfH in their axons are promising links to studies promoting high levels of pNfH in the cerebrospinal fluid (CSF) as an early hallmark of ALS in humans. KeywordsDorsal root ganglia, Amyotrophic lateral sclerosis, Wobbler, Neurofilaments, Neurodegeneration IntroductionNeurological diseases, and in particular motor neuron diseases (MND), have a great impact on a patient's quality of life. ALS is a common MND with an incidence of 1-3 cases per 100.000 per year and a prevalence of 3-8 per 100.000, with men being more often affected than women. The average survival is 3 years after the onset of ALS symptoms, typically between the ages of 55 to 60 [1]. Many pathological mechanisms have already been well investigated in animal models with ALS-like phenotypes, however comparison to the human ALS pathology is difficult. A treatment substantially modifying the diseases progression is still lacking. The well-known degeneration of the upper and lower motor neurons are common in the murine models as well as in humans. This

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“…The decreased GARP stability leads to impaired retrograde vesicle traffic and enlarged endosomal structures in the motor neuron [ 3 , 16 ]. Homozygous ( wr/wr ) mice exhibit progressive locomotor impairment with corresponding muscle atrophy, hyperreflexia, weakness, cramps, and ultimately respiratory failure caused by degenerative motor neurons in the spinal cord, brain stem, and motor cortex, whereas the (wobbler) WR mice show no clinical abnormalities during the first 3 weeks after birth (pre-symptomatic period) [ 17 , 18 ]. At the age of 4 weeks to 3 months, the WR mice are conspicuous due to a reduced body weight, slightly unsteady gait, fine head tremor, and muscle atrophy, predominantly in the face and forelimbs [ 12 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Inflammation and neuronal death in the motor cortex of the wobbler mouse, an ALS animal model

Dahlke

Saberi

Ott

et al. 2015

J Neuroinflammation

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BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of the upper and lower motor neurons, characterized by rapid progressive weakness, muscle atrophy, dysarthria, dysphagia, and dyspnea. Whereas the exact cause of ALS remains uncertain, the wobbler mouse (phenotype WR; genotype wr/wr) equally develops a progressive degeneration of motor neurons in the spinal cord and motor cortex with striking similarities to sporadic human ALS, suggesting the possibility of a common pathway to cell death.MethodsWith the aid of immunohistochemistry, confocal laser scanning microscopy, and transmission electron microscopy techniques, we analyze the proliferation behavior of microglial cells and astrocytes. We also investigate possible motor neuron death in the mouse motor cortex at different stages of the wobbler disease, which so far has not received much attention.ResultsAn abnormal density of Iba-1-positive microglial cells expressing pro-inflammatory tumor necrosis factor (TNF) alpha- and glial fibrillary acidic protein (GFAP)-positive activated astroglial cells was detected in the motor cortex region of the WR mouse 40 days postnatal (d.p.n.). Motor neurons in the same area show caspase 3 activation indicating neurodegenerative processes, which may cause progressive paralysis of the WR mice. It could also cause cell degeneration, such as vacuolization, dilation of the ER, and swollen mitochondria at the same time, and support the assumption that inflammation might be an important contributing factor of motor neuron degeneration. This would appear to be confirmed by the fact that there was no conspicuous increase of microglial cells and astrocytes in the motor cortex of control mice at any time.ConclusionsActivated microglial cells secrete a variety of pro-inflammatory and neurotoxic factors, such as TNF alpha, which could initiate apoptotic processes in the affected wobbler motor neurons, as reflected by caspase 3 activation, and thus, the neuroinflammatory processes might influence or exacerbate the neurodegeneration. Although it remains to be clarified whether the immune response is primary or secondary and how harmful or beneficial it is in the WR motor neuron disease, anti-inflammatory treatment might be considered.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0435-0) contains supplementary material, which is available to authorized users.

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Implementation of a manual for working with wobbler mice and criteria for discontinuation of the experiment

Cited by 19 publications

References 19 publications

VPS54 and the wobbler mouse

VPS54 and the wobbler mouse

Morphological Studies of Wobbler Mouse Dorsal Root Ganglia Show Neurofilamental Disorders

Inflammation and neuronal death in the motor cortex of the wobbler mouse, an ALS animal model

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