Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

Douglas, Darlene S.; Popko, Brian

doi:10.1007/s11064-008-9719-4

Cited by 12 publications

(8 citation statements)

References 100 publications

(139 reference statements)

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“…DPN is the most frequently occurring chronic complication of diabetes and is associated with significant morbidity and mortality in diabetes patients (16). Various theories have been proposed concerning the pathogenesis of DPN, including oxidative stress, polyol pathway activation, increased amounts of advanced glycation end products, protein kinase C and MAPK activation, increased levels of inflammatory cytokines, including TNF-α and IL-6, and neurotrophic factor deficiency (1,(17)(18)(19)(20)(21)(22). Among the various theories concerning the pathogenesis of DPN, the pathway most vital for the development and progression of DPN appears to be that of inflammation (1).…”

Section: Discussionmentioning

confidence: 99%

GLP‑1R agonists ameliorate peripheral nerve dysfunction and inflammation via p38 MAPK/NF‑κB signaling pathways in streptozotocin‑induced diabetic rats

Shi

Zhang

et al. 2018

Int J Mol Med

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The present study aimed to investigate the mechanism of glucagon‑like peptide‑1 receptor (GLP‑1R) agonists in the progression of diabetic peripheral neuropathy (DPN) in streptozotocin (STZ)‑induced diabetic rats, through inflammatory signaling pathways. The DPN rat model was generated by intraperitoneal injection of STZ and then treated with the GLP‑1R agonist liraglutide or saline for 8 weeks. These animals were randomly divided into 4 groups (10 rats in each): The normal control + saline group, the normal control + liraglutide group, the diabetic + saline (DM) group and the diabetic + liraglutide (DML) group. The nerve conduction velocity (NCV) in the sciatic nerves of the rats was monitored over a period of 8 weeks. Peripheral serum was obtained for the measurement of blood glucose, tumor necrosis factor‑α (TNF‑α), interleukin‑6 (IL‑6) and IL‑1β level. The protein levels of phosphorylated (p‑) and total extracellular signal‑regulated kinase, c‑Jun NH2‑terminal kinases, p38 mitogen‑activated protein kinases (MAPK), and nuclear and cytoplasmic nuclear factor‑κB (NF‑κB) were measured through western blot analysis. Sciatic nerve mRNA expression levels of proinflammatory chemokines (TNF‑α, IL‑6 and IL‑1β), chemokines [monocyte chemoattractant protein‑1 (MCP‑1)], adhesion molecules [intercellular adhesion molecule 1 (ICAM‑1)], neurotrophic factors [neuritin, nerve growth factor (NGF) and neuron‑specific enolase (NSE)] and NADPH oxidase 4 (NOX4) were evaluated by reverse transcription-quantitative polymerase chain reaction. Subsequent to 8 weeks of treatment with liraglutide, the density of myelin nerve fibers was partially restored in the DML group. The delayed motor NCV and sensory NCV in the DML group were improved. The IOD value of NOX4 staining in the DML group (24.43±9.01) was reduced compared with that in the DM group (56.60±6.91). The levels of TNF‑α, IL‑1β and IL‑6 in the peripheral serum of the DML group were significantly suppressed compared with those of the DM group. It was also observed that the mRNA expression levels of TNF‑α, IL‑6, IL‑1β, MCP‑1, ICAM‑1 and NOX4 in the sciatic nerve were attenuated in the DML group. The mRNA expression of neuritin and NGF was significantly increased in the DML group compared with that of the DM group; NSE was reduced in the sciatic nerves of the DML group compared with that of the DM group. Additionally, the protein expression of p‑p38 MAPK and NF‑κB in the DML group was significantly suppressed. These data demonstrated that GLP‑1R agonists may prevent nerve dysfunction in the sciatic nerves of diabetic rats via p38 MAPK/NF‑κB signaling pathways independent of glycemic control. GLP‑1R agonists may be a useful therapeutic strategy for slowing the progression of DPN.

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Section: Discussionmentioning

confidence: 99%

GLP‑1R agonists ameliorate peripheral nerve dysfunction and inflammation via p38 MAPK/NF‑κB signaling pathways in streptozotocin‑induced diabetic rats

Shi

Zhang

et al. 2018

Int J Mol Med

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“…Mitochondrial dysfunction and apoptosis are considered as the major cellular mechanisms in muscular dystrophy of mice [ 4 , 29 , 33 , 34 ]. Mitochondria in muscular dystrophy are highly permeable to protons that are unfavorable for the build-up of transmembrane proton gradients.…”

Section: Discussionmentioning

confidence: 99%

Remodeling of Mitochondrial Flashes in Muscular Development and Dystrophy in Zebrafish

et al. 2015

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Mitochondrial flash (mitoflash) is a highly-conserved, universal, and physiological mitochondrial activity in isolated mitochondria, intact cells, and live organisms. Here we investigated developmental and disease-related remodeling of mitoflash activity in zebrafish skeletal muscles. In transgenic zebrafish expressing the mitoflash reporter cpYFP, in vivo imaging revealed that mitoflash frequency and unitary properties underwent multiphasic and muscle type-specific changes, accompanying mitochondrial morphogenesis from 2 to 14 dpf. In particular, short (S)-type mitoflashes predominated in early muscle formation, then S-, transitory (T)- and regular (R)-type mitoflashes coexisted during muscle maturation, followed by a switch to R-type mitoflashes in mature skeletal muscles. In early development of muscular dystrophy, we found accelerated S- to R-type mitoflash transition and reduced mitochondrial NAD(P)H amidst a remarkable cell-to-cell heterogeneity. This study not only unravels a profound functional and morphological remodeling of mitochondria in developing and diseased skeletal muscles, but also underscores mitoflashes as a useful reporter of mitochondrial function in milieu of live animals under physiological and pathophysiological conditions.

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“…The role of Dst in neurological and skin diseases has been highlighted through analyses of various mutants: spontaneous mutant mice [ Dst dt (Duchen et al ., , ), Dst dt‐alb (Messer & Strominger, ), and Dst dt‐Frk (Pool et al ., )], knockout mouse [ Dst tm1Efu (Guo et al ., )], an insertional mouse mutant [ Dst Tg4 (Kothary et al ., ; Ichikawa et al ., )] as well as the human genetic skin disease epidermolysis bullosa simplex (OMIM 615425) (Groves et al ., ) and neurological disease, including hereditary sensory and autonomic neuropathy type 6 (OMIM 614653) (Edvardson et al ., ). It is notable that the causative DNA mutations in most spontaneous rodent dt mutants have not yet been identified (Douglas & Popko, ). The roles of the Dst isoforms in the nervous system and the neuronal network responsible for the neurological manifestations can be better understood by employing isoform(s)‐specific and/or conditional‐targeted mouse models.…”

Section: Introductionmentioning

confidence: 99%

Disruption of actin‐binding domain‐containing Dystonin protein causes dystonia musculorum in mice

Horie

Watanabe

Bepari

et al. 2014

Eur J of Neuroscience

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The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst-a isoforms, which contain actin-binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well-recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin-binding domain-containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (Dst(Gt) ) encodes a mutant Dystonin-LacZ fusion protein, which is detectable by X-gal (5-bromo-4-chloro-3-indolyl-β-D-galactoside) staining. We observed wide expression of the actin-binding domain-containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell-autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar-thalamo-striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel Dst(Gt) mice showed that a loss-of-function mutation in the actin-binding domain-containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose Dst(Gt) allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype.

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Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

Cited by 12 publications

References 100 publications

GLP‑1R agonists ameliorate peripheral nerve dysfunction and inflammation via p38 MAPK/NF‑κB signaling pathways in streptozotocin‑induced diabetic rats

GLP‑1R agonists ameliorate peripheral nerve dysfunction and inflammation via p38 MAPK/NF‑κB signaling pathways in streptozotocin‑induced diabetic rats

Remodeling of Mitochondrial Flashes in Muscular Development and Dystrophy in Zebrafish

Disruption of actin‐binding domain‐containing Dystonin protein causes dystonia musculorum in mice

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