The Spatiotemporal Pattern of Degeneration in the Cerebellum of the Wobbler Mouse

Saberi, Darius; Ott, Bastian; Dahlke, Carolin; Matschke, Veronika; Schmitt-John, Thomas; Theiß, Carsten

doi:10.1093/jnen/nlw005

Cited by 17 publications

(19 citation statements)

References 47 publications

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“…Even though the cerebellum does not initiate any movements, its influence on fine-tuning, precision, and timing of motion sequences is crucial. Although ALS is considered as a multifactorial disease [21,22,23], the cerebellum shows no signs of neurodegeneration in the three-layered cortex besides some marginal alterations like p62-positive cytosolic inclusions as well as minimal astro- and microgliosis [24,25,26]. However, structural and functional changes of the cerebellum have been demonstrated [27,28,29,30].…”

Section: Introductionmentioning

confidence: 99%

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Deregulated miR-29b-3p Correlates with Tissue-Specific Activation of Intrinsic Apoptosis in An Animal Model of Amyotrophic Lateral Sclerosis

Klatt

Theis

Hahn

et al. 2019

Cells

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Amyotrophic lateral sclerosis (ALS) is one of the most common incurable motor neuron disorders in adults. The majority of all ALS cases occur sporadically (sALS). Symptoms of ALS are caused by a progressive degeneration of motor neurons located in the motor cortex and spinal cord. The question arises why motor neurons selectively degenerate in ALS, while other cells and systems appear to be spared the disease. Members of the intrinsic apoptotic pathway are frequent targets of altered microRNA expression. Therefore, microRNAs and their effects on cell survival are subject of controversial debates. In this study, we investigated the expression of numerous members of the intrinsic apoptotic cascade by qPCR, western blot, and immunostaining in two different regions of the CNS of wobbler mice. Further we addressed the expression of miR-29b-3p targeting BMF, Bax, and, Bak, members of the apoptotic pathway. We show a tissue-specific differential expression of BMF, Bax, and cleaved-Caspase 3 in wobbler mice. An opposing regulation of miR-29b-3p expression in the cerebellum and cervical spinal cord of wobbler mice suggests different mechanisms regulating the intrinsic apoptotic pathway. Based on our findings, it could be speculated that miR-29b-3p might regulate antiapoptotic survival mechanisms in CNS areas that are not affected by neurodegeneration in the wobbler mouse ALS model.

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Section: Introductionmentioning

confidence: 99%

“…After p20, the first symptoms, such as head tremor, unsteady gait or muscle weakness of the front limps start to arise [12,33]. At p40, the WR phenotype is fully developed and stagnate [25]. In this study, we chose to solely focus on the presymptomatic and the stable phase.…”

Section: Introductionmentioning

confidence: 99%

Deregulated miR-29b-3p Correlates with Tissue-Specific Activation of Intrinsic Apoptosis in An Animal Model of Amyotrophic Lateral Sclerosis

Klatt

Theis

Hahn

et al. 2019

Cells

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“…IL1B gene encodes for the proinflammatory cytokine interleukin-1β (IL-1β), which belongs to member of IL-1 family and is produced by several cell types including blood monocytes, tissue macrophages and cells of the central nervous system [39]. It has been found mediating chronic inflammation in neurodegenerative conditions, such as Parkinson’s disease [40, 41], Amyotrophic lateral sclerosis [42], Alzheimer’s disease [43, 44] and neurodegenerative process in inflammatory disease such as multiple sclerosis [45].…”

Section: Discussionmentioning

confidence: 99%

IL1B polymorphism is associated with essential tremor in Chinese population

Chen

Huang

et al. 2019

BMC Neurol

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Background The aim of the study was to investigate the genetic risk factors of essential tremor (ET) in Chinese Population. Methods A total of 225 ET patients (25 ET patients also had restless legs syndrome (RLS) and were excluded from final analysis) and 229 controls were recruited. The diagnosis of ET was based on the Consensus Statement of the Movement Disorders Society on tremor. Polymerase chain reaction (PCR) and sequencing were used to detect 12 single nucleotide polymorphisms (SNPs) in seven candidate genes for RLS ( HMOX1, HMOX2, VDR, IL17A, IL1B, NOS1 and ADH1B). Results We found that one SNP was associated with the risk of ET in Chinese population after adjusting for age and gender: rs1143633 of IL1B (odds ratio [OR] =2.57, p = 0.003, recessive model), and the statistical result remained significant after Bonferroni correction. Then, we performed a query in Genotype-tissue Expression (GTEx), Brain eQTL Almanac (Braineac) databases and Blood expression quantitative trait loci (eQTL) browser. The significant association was only found between genotype at rs1143633 and IL1B expression level of putamen and white matter in Braineac database, which was more prominent with homozygous (GG) carriers. Conclusions Our study firstly reported the association of IL1B polymorphism with the risk of ET in Chinese population. However, the association might only suggest a marker of IL1B SNP associated with ET instead of the casual variant. Further studies are needed to confirm our finding. Electronic supplementary material The online version of this article (10.1186/s12883-019-1331-5) contains supplementary material, which is available to authorized users.

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“…Since first being described by Charcot in 1896, ALS has been investigated intensively and many cellular defects found in animal models have been suggested to cause these symptoms, such as oxidative stress due to mitochondrial dysfunction, protein aggregation, neuroinflammation in different parts of the central nervous system and impaired axonal transport [2][3][4][5][6]. Up till now, none of the cellular defects found have led to a strategy to modify disease progression in animal models or humans.…”

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 Spatiotemporal Pattern of Degeneration in the Cerebellum of the Wobbler Mouse

Cited by 17 publications

References 47 publications

Deregulated miR-29b-3p Correlates with Tissue-Specific Activation of Intrinsic Apoptosis in An Animal Model of Amyotrophic Lateral Sclerosis

Deregulated miR-29b-3p Correlates with Tissue-Specific Activation of Intrinsic Apoptosis in An Animal Model of Amyotrophic Lateral Sclerosis

IL1B polymorphism is associated with essential tremor in Chinese population

Morphological Studies of Wobbler Mouse Dorsal Root Ganglia Show Neurofilamental Disorders

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