Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43

Stribl, Carola; Samara, Aladin; Trümbach, Dietrich; Peis, Regina; Neumann, Manuela; Fuchs, Helmut; Gailus‐Durner, Valérie; Angelis, Martin Hrabé de; Rathkolb, Birgit; Wolf, Eckhard; Beckers, Johannes; Horsch, Marion; Neff, Frauke; Kremmer, Elisabeth; Koob, Sebastian; Reichert, Andreas S.; Hans, Wolfgang; Rozman, Jan; Klingenspor, Martin; Aichler, Michaela; Walch, Axel; Becker, Lore; Klopstock, Thomas; Glasl, Lisa; Hölter, Sabine M.; Wurst, Wolfgang; Floss, Thomas

doi:10.1074/jbc.m113.515940

Cited by 104 publications

(66 citation statements)

References 97 publications

(79 reference statements)

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“…From a therapeutic perspective, this variability can have tremendous implications with regard to the possible range of heterozygosity on disease expression (Bonneau et al, 2014). In other words, even if the trait is recessive, there may be other downstream consequences associated with being a carrier of just one recessive gene (e.g., Stribl et al, 2014). Potentially, this variability may also be associated with tissue-specific gene expression (Lo et al, 2003;Loeuillet et al, 2007;Zhang et al, 2009,).…”

Section: Discussionmentioning

confidence: 99%

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

Myers

Martinez

et al. 2015

Drug Metab Dispos

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Thirty-three Collies (14 male and 19 female) were used in a doseescalation study to determine the impact of ABCB1 genotype on loperamide pharmacokinetics (PK) and pharmacodynamics (PD). Loperamide was orally administered in four ascending doses (0.01, 0.05, 0.1, or 0.2 mg/kg) over a 4-wk period to fasted Collies. Comparisons were made within each dose to genotype, phenotype, and whether Collies received three (3D) or four (4D) loperamide doses. The 3D and 4D groupings had statistically significant differences in systemic drug exposure (defined by the area under the concentration-versus-time profile estimated from time zero to the last quantifiable drug concentration, AUC 0-last ). In contrast, statistical differences in AUC 0-last only occurred in the comparison between wild-type (WT) Collies versus homozygous mutant (Mut) Collies administered 0.1 mg/kg. Statistical differences in the proportionality relationship were observed when comparing 3D to 4D Collies, and the WT to Mut Collies. Intersubject variability in drug exposure tended to be twice as high between Mut and WT Collies. Associations were observed between systemic drug exposure and ataxia or depression but not between systemic drug exposure and mydriasis or salivation. Thus, Collies expressing the greatest sensitivity to CNS-associated effects of loperamide (Mut) tended to have higher drug exposure compared with those less sensitive to the adverse effects of loperamide. Genotype and phenotype only partially explained differences in loperamide PK and PD, suggesting this relationship may not be straightforward and that other factors need to be considered. Accordingly, the PD and PK of one P-glycoprotein substrate only partially predicted the likelihood of adverse responses to unrelated substrates.

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Section: Discussionmentioning

confidence: 99%

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

Myers

Martinez

et al. 2015

Drug Metab Dispos

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“…Subsequently, J. Lu et al demonstrate that both human TDP-43 and mutant TDP-43 cause morphological dysfunctions; they also demonstrate a decreased activity of complex I of respiratory chain and loss of transmembrane potential of mitochondria [81]. Neurons of heterozygous hTDP-43 A315T mice show significant mitochondrial dysmorphology with reduced ability of cristae formation [82]. It is reasonable to predict that misfolded TDP-43 may perturb mitochondrial function in AD as well as in FTLD/ALS.…”

Section: The Role Of Tdp-43 In Mitochondrial Dysfunctionmentioning

confidence: 99%

The Role of TDP-43 in Alzheimer’s Disease

Chang

Tan

et al. 2015

Mol Neurobiol

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The transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U, also known as FTLD-TDP). Several studies have indicated TDP-43 deposits in Alzheimer's disease (AD) brains and have robust connection with AD clinical phenotype. FTLD-U, which was symptomatically connected with AD, may be predictable for the comprehension of the role TDP-43 in AD. TDP-43 may contribute to AD through both β-amyloid (Aβ)-dependent and Aβ-independent pathways. In this article, we summarize the latest studies concerning the role of TDP-43 in AD and explore TDP-43 modulation as a potential therapeutic strategy for AD. However, to date, little of pieces of the research on TDP-43 have been performed to investigate the role in AD; more investigations need to be confirmed in the future.

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“…Like SOD1 G93A mice, transgenic mice overexpressing wild-type or mutant TDP-43 also exhibit mitochondrial aggregation in spinal motor neurons (40,41). Similarly, in mice, knock-in of the human TDP-43 A315T mutant promotes formation of ubiquitin-positive inclusion bodies containing TDP-43 in the spinal cord and abnormal mitochondrial structure in motor cortex neurons (44). Taken together, aberrant cytosolic localization of either wild-type or mutant forms of TDP-43 directly impairs mitochondrial function.…”

Section: Amyotrophic Lateral Sclerosis and Mitochondrial Dysfunctionmentioning

confidence: 99%

The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis

Fukunaga

Shinoda

Tagashira

2015

Journal of Pharmacological Sciences

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Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.304G > C), which encodes sigma-1 receptor (Sig-1R), substituting glutamine for glutamic acid at amino acid residue 102 (p.E102Q). Expression of that mutant Sig-1R(E102Q) protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death in neuro2A cells. In this issue, we discuss mechanisms underlying mitochondrial impairment seen in ALS motor neurons and propose that therapies that protect mitochondria might improve the quality of life (QOL) of ALS patients and should be considered for clinical trials.

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Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43

Cited by 104 publications

References 97 publications

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

The Role of TDP-43 in Alzheimer’s Disease

The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis

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