The Potential of Indole and a Synthetic Derivative for PolyQ Aggregation Reduction by Enhancement of the Chaperone and Autophagy Systems

Lin, Chin‐Feng; Wu, Yih Ru; Kung, Pin-Jui; Chen, Wan Ling; Lee, Li Ching; Lin, Tianquan; Chao, Chuck C.‐K.; Chen, Chiung Mei; Chang, Kuo Hsuan; Janreddy, Donala; Lee-Chen, Guey Jen; Yao, Ching Fa

doi:10.1021/cn500075u

Cited by 22 publications

(19 citation statements)

References 51 publications

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“…Therapeutic approaches vary, 4 but they typically fail to sufficiently alleviate symptoms. [5][6][7][8][9] Most degenerative ataxias feature Purkinje cell loss, 10,11 resulting in modified inputs to the deep cerebellar nuclei; thus, neuromodulation targeting these deep cerebellar nuclei may succeed in numerous DCAs.…”

mentioning

confidence: 99%

Deep cerebellar stimulation reduces ataxic motor symptoms in the shaker rat

Anderson¹,

Figueroa²,

Dorval

et al. 2019

Annals of Neurology

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Objective: Degenerative cerebellar ataxias (DCAs) affect up to 1 in 5,000 people worldwide, leading to incoordination, tremor, and falls. Loss of Purkinje cells, nearly universal across DCAs, dysregulates the dentatothalamocortical network. To address the paucity of treatment strategies, we developed an electrical stimulation-based therapy for DCAs targeting the dorsal dentate nucleus. Methods: We tested this therapeutic strategy in the Wistar Furth shaker rat model of Purkinje cell loss resulting in tremor and ataxia. We implanted shaker rats with stimulating electrodes targeted to the dorsal dentate nucleus and tested a spectrum of frequencies ranging from 4 to 180 Hz. Results: Stimulation at 30 Hz most effectively reduced motor symptoms. Stimulation frequencies >100 Hz, commonly used for parkinsonism and essential tremor, worsened incoordination, and frequencies within the tremor physiologic range may worsen tremor. Interpretation: Low-frequency deep cerebellar stimulation may provide a novel strategy for treating motor symptoms of degenerative cerebellar ataxias.

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mentioning

confidence: 99%

Deep cerebellar stimulation reduces ataxic motor symptoms in the shaker rat

Anderson¹,

Figueroa²,

Dorval

et al. 2019

Annals of Neurology

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“…The collection from the UrFU was employed to search for the activators of Hsp70 synthesis; the chemicals were selected based on the similarity of their domain to the indole-like pharmacophore found earlier that increased the Hsp70 level [35]. We used the reporter assay comprised of rat C6 glioma cells expressing the luciferase gene under the control of the HSE promotor.…”

Section: Identification Of Hsp70 Inducersmentioning

confidence: 99%

Pyrrolylquinoxaline-2-One Derivative as a Potent Therapeutic Factor for Brain Trauma Rehabilitation

et al. 2020

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Traumatic brain injury (TBI) often causes massive brain cell death accompanied by the accumulation of toxic factors in interstitial and cerebrospinal fluids. The persistence of the damaged brain area is not transient and may occur within days and weeks. Chaperone Hsp70 is known for its cytoprotective and antiapoptotic activity, and thus, a therapeutic approach based on chemically induced Hsp70 expression may become a promising approach to lower post-traumatic complications. To simulate the processes of secondary damage, we used an animal model of TBI and a cell model based on the cultivation of target cells in the presence of cerebrospinal fluid (CSF) from injured rats. Here we present a novel low molecular weight substance, PQ-29, which induces the synthesis of Hsp70 and empowers the resistance of rat C6 glioma cells to the cytotoxic effect of rat cerebrospinal fluid taken from rats subjected to TBI. In an animal model of TBI, PQ-29 elevated the Hsp70 level in brain cells and significantly slowed the process of the apoptosis in acceptor cells in response to cerebrospinal fluid action. The compound was also shown to rescue the motor function of traumatized rats, thus proving its potential application in rehabilitation therapy after TBI.

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“…Hsp40 overexpression decreased mutant ataxin-3 aggregation while increasing its levels in cells, prompting the hypothesis that Hsp40 may bind mutant ataxin-3 and delay its degradation [33]. Hsp70 overexpression decreased mutant protein aggregation in SCA3, SCA7 and DRPLA cellular models [128,204,205]. In a SCA3 Drosophila model, overexpression of Hsp40 or Hsp70 reduced mutant ataxin-3 induced toxicity.…”

Section: Genetic Modulation Of Molecular Chaperones In Scas and Drplamentioning

confidence: 99%

“…Treatment with GGA decreased mutant protein aggregation in SCA3 and SCA17 cells [205,210], but had no effect on mutant ataxin-3 toxicity in SCA3 Drosophila [141]. Indole and its derivate NC001-8 were recently tested in SCA models.…”

Section: Pharmacological Modulation Of Molecular Chaperones In Scas Amentioning

confidence: 99%

“…Indole and its derivate NC001-8 were recently tested in SCA models. Although the mechanisms by which these compounds induce chaperone expression remain uncertain, both decreased mutant protein aggregation in SCA3 and SCA17 cells [205,210], being reported to enhance autophagy in SCA3 cells [205].…”

Section: Pharmacological Modulation Of Molecular Chaperones In Scas Amentioning

confidence: 99%

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Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

2016

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Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs, and suggests different interactions with the cellular proteostasis machinery. Molecular chaperones are key elements of the proteostasis machinery and therapeutic targets for neurodegeneration. Here we provide a focused review on Hsp90, Hsp70, and their cochaperones, and how their genetic or pharmacological modulation affects the proteostasis and disease phenotypes in cellular and animal models of polyglutamine disorders. The emerging picture is that, in principle, Hsp70 modulation may be more amenable for long-term treatment by promoting a more selective clearance of mutant proteins than Hsp90 modulation, which may further decrease the necessary wild-type counterparts. It seems, nevertheless, unlikely that a single Hsp70 modulator will benefit all polyglutamine diseases. Indeed, available data, together with insights from effects on tau and alpha-synuclein in models of Alzheimer's and Parkinson's diseases, indicates that Hsp70 modulators may lead to different effects on the proteostasis of different mutant and wild-type client proteins. Future studies should include the further development of isoform selective inhibitors, namely to avoid off-target effects on Hsp in the mitochondria, and their characterization in distinct polyglutamine disease models to account for client protein-specific differences.

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The Potential of Indole and a Synthetic Derivative for PolyQ Aggregation Reduction by Enhancement of the Chaperone and Autophagy Systems

Cited by 22 publications

References 51 publications

Deep cerebellar stimulation reduces ataxic motor symptoms in the shaker rat

Deep cerebellar stimulation reduces ataxic motor symptoms in the shaker rat

Pyrrolylquinoxaline-2-One Derivative as a Potent Therapeutic Factor for Brain Trauma Rehabilitation

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

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