Normal Mitochondrial DNA and Respiratory Chain Activity in Familial Dysautonomia Fibroblasts

Strasberg, Paula M.; Bridge, Phillipa; Merante, Frank; Yeger, Herman; Pereira, Jude

doi:10.1006/bmme.1996.0059

Cited by 7 publications

(4 citation statements)

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“…Cultured FD fibroblasts have shown no mitochondrial dysfunction. 16 On the other hand, in a retrospective review of our database, we found a 14-year-old boy with FD in whom activity levels of complex I, III, and IV mitochondrial enzymes in muscle were decreased, suggesting an electron transport chain disorder. Mitochondrial DNA analysis disclosed no mutations.…”

Section: Discussionmentioning

confidence: 72%

Increased frequency of rhabdomyolysis in familial dysautonomia

Palma

Roda

2015

Muscle and Nerve

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Background Familial dysautonomia (FD, OMIM# 223900) is an autosomal recessive disease featured by impaired pain and temperature perception and lack of functional muscle spindles. After 3 FD patients presented with rhabdomyolysis in a short time span, we aimed to determine the frequency of rhabdomyolysis is this population. Methods and Results In a retrospective chart review of 665 FD patients, 8 patients had at least 1 episode of rhabdomyolysis. Two patients had 2 episodes. The average incidence of rhabdomyolysis in FD was 7.5 per 10,000 person-years. By comparison, the average incidence with statins has been reported to be 0.44 per 10,000 person-years. Mean maximum creatine kinase (CK) level was 32,714 ± 64,749 U/l. Three patients had a hip magnetic resonance imaging showing gluteal hyperintensities. Conclusions Patients with FD have an increased incidence of rhabdomyolysis. We hypothesize that this may result from a combination of absent functional muscle spindles and muscle mitochondrial abnormalities.

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Section: Discussionmentioning

confidence: 72%

Increased frequency of rhabdomyolysis in familial dysautonomia

Palma

Roda

2015

Muscle and Nerve

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“…The mitochondrial depolarization was determined by MitoTracker Red fluorochrome detection method [35,36]. Figure 4 panel B2-3, depict an increase in the depolarization of mitochondria in a dose-dependent manner with the addition of 3 nM or 25 nM/ml of recombinant Nef protein.…”

Section: Resultsmentioning

confidence: 99%

Combined effects of hyperglycemic conditions and HIV-1 Nef: a potential model for induced HIV neuropathogenesis

Acheampong¹,

Roschel

Mukhtar

et al. 2009

Virol J

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Hyperglycemic conditions associated with diabetes mellitus (DM) or with the use of antiretroviral therapy may increase the risk of central nervous system (CNS) disorders in HIV-1 infected patients. In support of this hypothesis, we investigated the combined effects of hyperglycemic conditions and HIV-1 accessory protein Nef on the CNS using both in vitro and in vivo models. Astrocytes, the most abundant glial cell type required for normal synaptic transmission and other functions were selected for our in vitro study. The results show that in vitro hyperglycemic conditions enhance the expression of proinflammatory cytokines including caspase-3, complement factor 3 (C3), and the production of total nitrate and 8-iso-PGF2 α as reactive oxygen species (ROS) in human astrocytes leading to cell death in a dose-dependent manner. Delivery of purified recombinant HIV-1 Nef protein, or Nef expressed via HIV-1-based vectors in astrocytes showed similar results. The expression of Nef protein delivered via HIV-1 vectors in combination with hyperglycemia further augmented the production of ROS, C3, activation of caspase-3, modulation of filamentous protein (F-protein), depolarization of the mitochondria, and loss of astrocytes. To further verify the effects of hyperglycemia and HIV-1 Nef protein on CNS individually or in combination, in vivo studies were performed in streptozotocin (STZ) induced diabetic mice, by injecting HIV-1 Nef expressing viral particles into the sub-cortical region of the brain. Our in vivo results were similar to in vitro findings indicating an enhanced production of caspases-3, ROS (lipid oxidation and total nitrate), and C3 in the brain tissues of these animals. Interestingly, the delivery of HIV-1 Nef protein alone caused similar damage to CNS as augmented by hyperglycemia conditions. Taken together, the data suggests that HIV-1 infected individuals with hyperglycemia could potentially be at a higher risk of developing CNS related complications.

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“…Studies in FD fibroblasts have been used to pursue a broad range of hypotheses on FD pathogenesis, such as changes in mitochondrial function [48] or neurotrophic factor secretion [49]. The more widely accepted differences in cell motility [41] and splicing [32] have also been first characterized in patientspecific fibroblasts.…”

Section: Towards An Induced Pluripotent Stem Cell Model Of Familial Dmentioning

confidence: 99%

“…Several cellular models of FD have been established over many years to study the human disease, including patient-specific fibroblast or lymphoblast cell lines. Studies in FD fibroblasts have been used to pursue a broad range of hypotheses on FD pathogenesis, such as changes in mitochondrial function [48] or neurotrophic factor secretion [49]. The more widely accepted differences in cell motility [41] and splicing [32] have also been first characterized in patientspecific fibroblasts.…”

Section: Towards An Induced Pluripotent Stem Cell Model Of Familial Dysautonomia (A) Traditional Cell-based Models Of Familial Dysautonommentioning

confidence: 99%

Modelling familial dysautonomia in human induced pluripotent stem cells

Lee

Studer

2011

Phil. Trans. R. Soc. B

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Induced pluripotent stem (iPS) cells have considerable promise as a novel tool for modelling human disease and for drug discovery. While the generation of disease-specific iPS cells has become routine, realizing the potential of iPS cells in disease modelling poses challenges at multiple fronts. Such challenges include selecting a suitable disease target, directing the fate of iPS cells into symptom-relevant cell populations, identifying disease-related phenotypes and showing reversibility of such phenotypes using genetic or pharmacological approaches. Finally, the system needs to be scalable for use in modern drug discovery. Here, we will discuss these points in the context of modelling familial dysautonomia (FD, Riley–Day syndrome, hereditary sensory and autonomic neuropathy III (HSAN-III)), a rare genetic disorder in the peripheral nervous system. We have demonstrated three disease-specific phenotypes in FD-iPS-derived cells that can be partially rescued by treating cells with the plant hormone kinetin. Here, we will discuss how to use FD-iPS cells further in high throughput drug discovery assays, in modelling disease severity and in performing mechanistic studies aimed at understanding disease pathogenesis. FD is a rare disease but represents an important testing ground for exploring the potential of iPS cell technology in modelling and treating human disease.

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Normal Mitochondrial DNA and Respiratory Chain Activity in Familial Dysautonomia Fibroblasts

Cited by 7 publications

References 0 publications

Increased frequency of rhabdomyolysis in familial dysautonomia

Increased frequency of rhabdomyolysis in familial dysautonomia

Combined effects of hyperglycemic conditions and HIV-1 Nef: a potential model for induced HIV neuropathogenesis

Modelling familial dysautonomia in human induced pluripotent stem cells

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