Inhibition of Drp1 hyper-activation is protective in animal models of experimental multiple sclerosis

Luo, Fucheng; Herrup, Karl; Qi, Xin; Yang, Yan

doi:10.1016/j.expneurol.2017.02.015

Cited by 59 publications

(62 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2B–E). Consistent with our previous studies [16,18], treatment with P110 had no significant effects on the behavioral status of wildtype mice through the study (Fig. 2).…”

Section: Resultssupporting

confidence: 92%

“…Myelin that is produced by oligodendrocytes wraps the axon and maintains the axonal function. Our previous study demonstrated that inhibition of Drp1 hyperactivation through P110 treatment reduced the loss of the mature oligodendrocytes and repaired demyelination in Multiple Sclerosis (MS) [18]. In zQ175 KI HD mice, we also observed a decrease in myelin basic protein (MBP), which was corrected by P110 treatment.…”

Section: Discussionmentioning

confidence: 86%

“…As previously described [14,16,18,19], the peptides are synthesized as one polypeptide with TAT 47–57 carrier in the following order: N-terminus-TAT–spacer (Gly-Gly)–cargo (Drp149–55)–C-terminus. The C-termini of the peptides are modified to C (O)-NH2 using Rink Amide AM resin to increase stability.…”

Section: Methodsmentioning

confidence: 99%

“…We recently developed the peptide inhibitor P110, which selectively inhibits the interaction between Drp1 and Fis1 under stressed conditions without affecting the physiological level of Drp1 [9,14,16]. We have demonstrated that treatment with P110 peptide abolished Drp1 translocation to the mitochondria and Drp1 polymerization, two markers of Drp1 hyperactivation, in models of HD [16], Parkinson’s disease (PD) [9,17], multiple sclerosis [18] and brain ischemia/reperfusion [8]. Notably, P110 treatment had no observed effects on animal behavioral status and survival rate of naïve mice [16,17], suggestive of less toxicity.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of Drp1 hyperactivation reduces neuropathology and behavioral deficits in zQ175 knock-in mouse model of Huntington's disease

Zhao

Sun

2018

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

Mitochondrial dysfunction manifests in the pathogenesis of Huntington’s disease (HD), a fatal and inherited neurodegenerative disease. Dynamin-related protein 1 (Drp1) is the primary component of mitochondrial fission and becomes hyperactivated in various models of HD. We previously reported that inhibition of Drp1 hyperactivation by P110, a rationally designed peptide inhibitor of Drp1-Fis1 interaction, is protective in the HD R6/2 mouse model, which expresses a fragment of mutant Huntingtin (mHtt). In this study, we expand our work to test the effect of P110 treatment in HD knock-in (zQ175 KI) mice that express full-length mtHtt and exhibit progressive disease symptoms, reminiscent of human HD. We find that subcutaneously sustained treatment with P110 reduces movement deficits of mice. Moreover, the treatment attenuates striatal neuronal loss, microglial hyperactivity and white matter disorganization in zQ175 KI mice. These findings provide an additional line of evidence that inhibition of Drp1 hyperactivation is sufficient to reduce HD-associated neuropathology and behavioral deficits. We propose that manipulation of Drp1 hyperactivation might be a useful strategy to develop therapeutics for treating HD.

show abstract

“…2B–E). Consistent with our previous studies [16,18], treatment with P110 had no significant effects on the behavioral status of wildtype mice through the study (Fig. 2).…”

Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Drp1 hyperactivation reduces neuropathology and behavioral deficits in zQ175 knock-in mouse model of Huntington's disease

Zhao

Sun

2018

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

show abstract

“…[3][4][5] Mitochondria are the main inducer and target of ROS. [3][4][5] Mitochondria are the main inducer and target of ROS.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of DNM1L and mitochondrial fission attenuates inflammatory response in fibroblast‐like synoviocytes of rheumatoid arthritis

Wang

Chen

Fan

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

Mitochondrial fission and fusion are important for mitochondrial function, and dynamin 1-like protein (DNM1L) is a key regulator of mitochondrial fission. We investigated the effect of mitochondrial fission on mitochondrial function and inflammation in fibroblast-like synoviocytes (FLSs) during rheumatoid arthritis (RA). DNM1L expression was determined in synovial tissues (STs) from RA and non-RA patients.FLSs were isolated from STs and treated with a DNM1L inhibitor (mdivi-1, mitochondrial division inhibitor 1) or transfected with DNM1L-specific siRNA. Mitochondrial morphology, DNM1L expression, cell viability, mitochondrial membrane potential, reactive oxygen species (ROS), apoptosis, inflammatory cytokine expression and autophagy were examined. The impact of mdivi-1 treatment on development and severity of collagen-induced arthritis (CIA) was determined in mice. Up-regulated DNM1L expression was associated with reduced mitochondrial length in STs from patients with RA and increased RA severity. Inhibition of DNM1L in FLSs triggered mitochondrial depolarization, mitochondrial elongation, decreased cell viability, production of ROS, IL-8 and COX-2, and increased apoptosis. DNM1L deficiency inhibited IL-1βmediated AKT/IKK activation, NF-κBp65 nuclear translocation and LC3B-related autophagy, but enhanced NFKBIA expression. Treatment of CIA mice with mdivi-1 decreased disease severity by modulating inflammatory cytokine and ROS production. Our major results are that up-regulated DNM1L and mitochondrial fission promoted survival, LC3B-related autophagy and ROS production in FLSs, factors that lead to inflammation by regulating AKT/IKK/NFKBIA/NF-κB signalling. Thus, inhibition of DNM1L may be a new strategy for treatment of RA. K E Y W O R D Sdynamin 1-like protein, fibroblast-like synoviocyte, inflammation, mitochondrial fission, rheumatoid arthritis | 1517 WANG et Al.

show abstract

Neuronal TNFα, Not α‐Syn, Underlies PDD‐Like Disease Progression in IFNβ‐KO Mice

Villanueva

Tresse

Liu

et al. 2021

Annals of Neurology

View full text Add to dashboard Cite

Objective: Parkinson's disease (PD) manifests in motor dysfunction, non-motor symptoms, and eventual dementia (PDD). Neuropathological hallmarks include nigrostriatal neurodegeneration, Lewy body (LB) pathology, and neuroinflammation. Alpha-synuclein (α-syn), a primary component of LBs, is implicated in PD pathogenesis, accumulating, and aggregating in both familial and sporadic PD. However, as α-syn pathology is often comorbid with amyloid-beta (Aβ) plaques and phosphorylated tau (pTau) tangles in PDD, it is still unclear whether α-syn is the primary cause of neurodegeneration in sporadic PDD. We aimed to determine how the absence of α-syn would affect PDD manifestation. Methods: IFN-β knockout (Ifnb À/À ) mice spontaneously develop progressive behavior abnormalities and neuropathology resembling PDD, notably with α-syn + LBs. We generated Ifnb/Snca double knockout (DKO) mice and evaluated their behavior and neuropathology compared with wild-type (Wt), Ifnb À/À , and Snca À/À mice using immunohistochemistry, electron microscopy, immunoblots, qPCR, and modification of neuronal signaling. Results: Ifnb/Snca DKO mice developed all clinical PDD-like behavioral manifestations induced by IFN-β loss. Independently of α-syn expression, lack of IFN-β alone induced Aβ plaques, pTau tangles, and LB-like Aβ + /pTau + inclusion bodies and neuroinflammation. IFN-β loss caused significant elevated glial and neuronal TNF-α and neuronal TNFR1, associated with neurodegeneration. Restoring neuronal IFN-β signaling or blocking TNFR1 rescued caspase 3/t-BIDmediated neuronal-death through upregulation of c-FLIP S and lowered intraneuronal Aβ and pTau accumulation. Interpretation: These findings increase our understanding of PD pathology and suggest that targeting α-syn alone is not sufficient to mitigate disease. Targeting specific aspects of neuroinflammation, such as aberrant neuronal TNF-α/TNFR1 or IFN-β/IFNAR signaling, may attenuate disease.

show abstract

Inhibition of Drp1 hyper-activation is protective in animal models of experimental multiple sclerosis

Cited by 59 publications

References 69 publications

Inhibition of Drp1 hyperactivation reduces neuropathology and behavioral deficits in zQ175 knock-in mouse model of Huntington's disease

Inhibition of Drp1 hyperactivation reduces neuropathology and behavioral deficits in zQ175 knock-in mouse model of Huntington's disease

Inhibition of DNM1L and mitochondrial fission attenuates inflammatory response in fibroblast‐like synoviocytes of rheumatoid arthritis

Neuronal TNFα, Not α‐Syn, Underlies PDD‐Like Disease Progression in IFNβ‐KO Mice

Contact Info

Product

Resources

About