Prevention of Huntington’s Disease-Like Behavioral Deficits in R6/1 Mouse by Tolfenamic Acid Is Associated with Decreases in Mutant Huntingtin and Oxidative Stress

Liu, Peng; Li, Yinjie; Yang, Wenli; Liu, Danyang; Ji, Xuefei; Chi, Tianyan; Guo, Zhutao; Li, Lin; Zou, Libo

doi:10.1155/2019/4032428

Cited by 19 publications

(35 citation statements)

References 41 publications

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“…Thus, the positive effect of ORM14 on mitochondrial morphology in OPA1 mutant cells may depend on a decrease in mitochondrial fission due to reduced CDK5 protein levels and, in turn, inhibition of DRP1. Recently, ORM14 treatment in a Huntington’s disease mouse model showed antioxidant properties, increasing the expression of NRF2, NQO1 and HO1, and also a pro-autophagic effect ( 66 ), as we also observed in R445H MEFs, suggesting that ORM14 may increase autophagic function in models of different diseases.…”

Section: Discussionsupporting

confidence: 70%

Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations

Aleo

Dotto

Fogazza

et al. 2020

Human Molecular Genetics

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OPA1 mutations are the major cause of Dominant Optic Atrophy (DOA) and the syndromic form DOA plus, pathologies for which there is no established cure. We used a ‘drug repurposing’ approach to identify FDA-approved molecules able to rescue the mitochondrial dysfunctions induced by OPA1 mutations. We screened two different chemical libraries by using two yeast strains carrying the mgm1I322M and the chim3P646L mutations, identifying twenty-six drugs able to rescue their oxidative growth phenotype. Six of them, able to reduce the mitochondrial DNA (mtDNA) instability in yeast, have been then tested in Opa1 deleted mouse embryonic fibroblasts (MEFs) expressing the human OPA1 isoform 1 bearing the R445H and D603H mutations. Some of these molecules were able to ameliorate the energetic functions and/or the mitochondrial network morphology, depending on the type of OPA1 mutation. The final validation has been performed in patients’ fibroblasts, allowing to select the most effective molecules. Our current results are instrumental to rapidly translating the findings of this drug repurposing approach into clinical trial for DOA and other neurodegenerations caused by OPA1 mutations.

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Section: Discussionsupporting

confidence: 70%

Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations

Aleo

Dotto

Fogazza

et al. 2020

Human Molecular Genetics

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“…Of note, the association between Bassoon and huntingtin inclusions was apparent already at the age of 16 weeks (Fig. 5a, b second panels) when the first motor symptoms appear in the R6/1 mouse model [10,17,22,25,46], implying the effect of colocalization induced the presynaptic dysfunction and led to locomotor impairment. At 40 weeks of age, the normal Bassoon signal was drastically reduced and the Bassoon protein seemed to be predominantly present in the mutant huntingtin aggregates (Fig.…”

Section: Bassoon Is Recruited To Huntingtin Aggregates In An Agedepenmentioning

confidence: 89%

No symphony without bassoon and piccolo: changes in synaptic active zone proteins in Huntington’s disease

Huang

Smith

Bacos

et al. 2020

acta neuropathol commun

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Prominent features of HD neuropathology are the intranuclear and cytoplasmic inclusions of huntingtin and striatal and cortical neuronal cell death. Recently, synaptic defects have been reported on HD-related studies, including impairment of neurotransmitter release and alterations of synaptic components. However, the definite characteristics of synapse dysfunction and the underlying mechanisms remain largely unknown. We studied the gene expression levels and patterns of a number of proteins forming the cytoskeletal matrix of the presynaptic active zones in HD transgenic mice (R6/1), in hippocampal neuronal cultures overexpressing mutant huntingtin and in postmortem brain tissues of HD patients. To investigate the interactions between huntingtin and active proteins, we performed confocal microscopic imaging and immunoprecipitation in mouse and HEK 293 cell line models. The mRNA and protein levels of Bassoon were reduced in mouse and cell culture models of HD and in brain tissues of patients with HD. Moreover, a striking redistribution of a complex of proteins including Bassoon, Piccolo and Munc 13-1 from the cytoplasm and synapses into intranuclear huntingtin aggregates with loss of active zone proteins and dendritic spines. This re-localization was agedependent and coincided with the formation of huntingtin aggregates. Using co-immunoprecipitation, we demonstrated that huntingtin interacts with Bassoon, and that this interaction is likely mediated by a third linking protein. Three structural proteins involved in neurotransmitter release in the presynaptic active zones of neurons are altered in expression and that the proteins are redistributed from their normal functional site into mutant huntingtin aggregates.

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“…Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by the abnormal expansion of the cytosine–adenine–guanine (CAG) repeat in the IT15 gene located on chromosome 4 [ 70 ]. This results in the production of mutant huntingtin (mHtt) protein with a long polyglutamine stretch in the N-terminus region of the Huntingtin protein (Htt) [ 70 , 71 ]. Individuals with greater than 39 CAG repeats develop HD, while those with 36–39 have reduced penetrance [ 71 ].…”

Section: Fenamates and Huntington’s Diseasementioning

confidence: 99%

“…The most common mouse model of HD is the R6 transgenic model that expresses a truncated form of the human Htt and has been used to examine therapeutic strategies [ 70 ]. The human htt gene is among many that are regulated by Sp1, which suggests that TA may be an effective treatment to attenuate motor and cognitive deficits for HD patients [ 74 ].…”

Section: Fenamates and Huntington’s Diseasementioning

confidence: 99%

Fenamates as Potential Therapeutics for Neurodegenerative Disorders

Hill

Zawia

2021

Cells

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Neurodegenerative disorders are desperately lacking treatment options. It is imperative that drug repurposing be considered in the fight against neurodegenerative diseases. Fenamates have been studied for efficacy in treating several neurodegenerative diseases. The purpose of this review is to comprehensively present the past and current research on fenamates in the context of neurodegenerative diseases with a special emphasis on tolfenamic acid and Alzheimer’s disease. Furthermore, this review discusses the major molecular pathways modulated by fenamates.

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Prevention of Huntington’s Disease-Like Behavioral Deficits in R6/1 Mouse by Tolfenamic Acid Is Associated with Decreases in Mutant Huntingtin and Oxidative Stress

Cited by 19 publications

References 41 publications

Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations

Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations

No symphony without bassoon and piccolo: changes in synaptic active zone proteins in Huntington’s disease

Fenamates as Potential Therapeutics for Neurodegenerative Disorders

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