The wobbler mouse, an ALS animal model

Moser, Jakob; Bigini, Paolo; Schmitt-John, Thomas

doi:10.1007/s00438-013-0741-0

Cited by 93 publications

(83 citation statements)

References 220 publications

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“…The wobbler mouse model has been derived from a spontaneous mutation in a mouse strain [105] and is caused by a point mutation of Vps54, a vesicle-tethering complex [106]. While the phenotype is similar to human ALS [107], a mutation that is similar to Vps54 has not been found in humans yet [108]. Currently existing ALS animal models are reviewed in more detail elsewhere [101].…”

Section: Limitations Of the Current Mouse Modelmentioning

confidence: 99%

Barriers to Novel Therapeutics in Amyotrophic Lateral Sclerosis

Kobeleva¹,

Petri²

2013

Neurodegen. Dis. Manage.

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Amyotrophic lateral sclerosis is a devastating neurodegenerative condition primarily involving the motor system in the cerebral cortex, brain stem and spinal cord, but can, in later disease stages, also affect distinct extramotor brain regions. In this article, we discuss the prevalent barriers, including clinical and genetic variability of amyotrophic lateral sclerosis, frailty of the current mouse model and inadequateness of clinical trials, in the search for novel therapeutics. Approaches in terms of understanding the pathogenesis, and the search for biomarkers to initiate early or even presymptomatic treatment and monitor treatment effects are highlighted.Amyotrophic lateral sclerosis (ALS) is a multisystem disease that not only affects the motor system, but also involves other brain areas such as the frontal lobes.The clinical ALS spectrum includes variable phenotypes that are defined by the affected body regions, involvement of the upper and lower motoneurons, and the speed of symptom progression.At present, riluzole is the only US FDA-approved drug for ALS. Its effect on survival is only moderate (2-3 months), augmenting the need for a more effective treatment.A large number of other compounds have not proven effective in clinical trials, owing to an incomplete understanding of the pathogenesis, phenotypic and genetic variability, and poor translation from animal models to humans.Various neurophysiological, biochemical and imaging biomarkers are currently being developed to support early diagnosis, monitor treatment effects and disease progression, and thus, improve the quality of clinical trials.

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Section: Limitations Of the Current Mouse Modelmentioning

confidence: 99%

Barriers to Novel Therapeutics in Amyotrophic Lateral Sclerosis

Kobeleva¹,

Petri²

2013

Neurodegen. Dis. Manage.

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“…Moreover, the serum glucocorticoid levels were significantly higher in SOD1 G93A mice at a terminal stage of illness and were negatively correlated with both disease onset and survival [42]. Additionally, wobbler mice, another rodent model for ALS [43], become vulnerable after adrenalectomy (surgical removal of the adrenal glands, which produce intrinsic glucocorticoids) [44]. Although these changes might be secondary rather than primary effects, further studies investigating how alterations in endogenous glucocorticoids after adrenalectomy influence the disease course in SOD1 G93A mice with or without Mt-I/-II are needed.…”

Section: G93amentioning

confidence: 99%

Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2015

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Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease. The pathogenesis of the disease is poorly understood, but intracellular copper dyshomeostasis has been implicated as a key process in the disease. We recently observed that metallothioneins (MTs) are an excellent target for the modification of copper dyshomeostasis in a mouse model of ALS (SOD1 G93A ). Here, we offer a therapeutic strategy designed to increase the level of endogenous MTs. The upregulation of endogenous MTs by dexamethasone, a synthetic glucocorticoid, significantly improved the disease course and rescued motor neurons in SOD1 G93A mice, even if the induction was initiated when peak body weight had decreased by 10 %. Neuroprotection was associated with the normalization of copper dyshomeostasis, as well as with decreased levels of SOD1 G93A aggregates. Importantly, these benefits were clearly mediated in a MT-dependent manner, as dexamethasone did not provide any protection when endogenous MTs were abolished from SOD1 G93A mice. In conclusion, the upregulation of endogenous MTs represents a promising strategy for the treatment of ALS linked to mutant SOD1.

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“…The wobbler mouse is an animal model of importance since it is considered as a model for sALS, representing approximately 90% of all ALS cases [7][8][9], although the wobbler mutation does not seem to be a common reason for ALS [10,11]. Palmisano and co-workers described enlarged vesicles in wobbler mice α-motor neurons (αMN) [12], which indicate an impaired trafficking in wobbler mice, like six out of fourteen human sALS cases.…”

Section: Immunofluorescence Staining Of Nfh/pnfhmentioning

confidence: 99%

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 wobbler mouse, an ALS animal model

Cited by 93 publications

References 220 publications

Barriers to Novel Therapeutics in Amyotrophic Lateral Sclerosis

Barriers to Novel Therapeutics in Amyotrophic Lateral Sclerosis

Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis

Morphological Studies of Wobbler Mouse Dorsal Root Ganglia Show Neurofilamental Disorders

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