Increased acetylation of Peroxiredoxin1 by HDAC6 inhibition leads to recovery of Aβ-induced impaired axonal transport

Choi, Heesun; Kim, Haeng Jun; Kim, Ji-Soo; Kim, Soohyun; Yang, Jinhee; Lee, Wonik; Park, Yeonju; Hyeon, Seung Jae; Lee, Dong Sup; Ryu, Hoon; Chung, Junho; Mook‐Jung, Inhee

doi:10.1186/s13024-017-0164-1

Cited by 59 publications

(52 citation statements)

References 54 publications

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“…The neuroprotective effects of HDAC6 inhibitors have been demonstrated in models of neurological disorders, including Alzheimer disease and Charcot-Marie-Tooth disease. [43][44][45] The neuroprotective effects of HDAC6 inhibitors in these models are associated with improved mitochondrial axonal transport and reduced oxidative damage. [43][44][45] We recently demonstrated that HDAC6 inhibitors prevent cisplatin-induced deficits in axonal mitochondrial transport in primary cultures of DRG neurons.…”

Section: Targeting Neuronal Mitochondrial Dysfunctionmentioning

confidence: 99%

“…[43][44][45] The neuroprotective effects of HDAC6 inhibitors in these models are associated with improved mitochondrial axonal transport and reduced oxidative damage. [43][44][45] We recently demonstrated that HDAC6 inhibitors prevent cisplatin-induced deficits in axonal mitochondrial transport in primary cultures of DRG neurons. 30 In vivo, the coadministration of an HDAC6 inhibitor with cisplatin prevented cisplatin-induced neuropathic pain.…”

Section: Targeting Neuronal Mitochondrial Dysfunctionmentioning

confidence: 99%

“…HDAC6 is a class IIB histone deacetylase that has limited effect on histones and acts mainly in the cytosol, in which it deacetylates tubulin, heat shock protein 90, and many other substrates. The neuroprotective effects of HDAC6 inhibitors have been demonstrated in models of neurological disorders, including Alzheimer disease and Charcot‐Marie‐Tooth disease . The neuroprotective effects of HDAC6 inhibitors in these models are associated with improved mitochondrial axonal transport and reduced oxidative damage .…”

Section: Introductionmentioning

confidence: 99%

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Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

Kavelaars

Dougherty

et al. 2018

Cancer

123

111

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Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting >60% of patients with cancer. Moreover, CIPN persists long into survivorship in approximately 20% to 30% of these patients. To the authors' knowledge, no drugs have been approved to date by the US Food and Drug Administration to effectively manage chemotherapy-induced neuropathic pain. The majority of the drugs tested for the management of CIPN aim at symptom relief, including pain and paresthesia, yet are not very efficacious. The authors propose that there is a need to acquire a more thorough understanding of the etiology of CIPN so that effective, mechanism-based, disease-modifying interventions can be developed. It is important to note that such interventions should not interfere with the antitumor effects of chemotherapy. Mitochondria are rod-shaped cellular organelles that represent the powerhouses of the cell, in that they convert oxygen and nutrients into the cellular energy "currency" adenosine triphosphate. In addition, mitochondria regulate cell death. Neuronal mitochondrial dysfunction and the associated nitro-oxidative stress represent crucial final common pathways of CIPN. Herein, the authors discuss the potential to prevent or reverse CIPN by protecting mitochondria and/or inhibiting nitro-oxidative stress with novel potential drugs, including the mitochondrial protectant pifithrin-μ, histone deacetylase 6 inhibitors, metformin, antioxidants, peroxynitrite decomposition catalysts, and anti-inflammatory mediators including interleukin 10. This review hopefully will contribute toward bridging the gap between preclinical research and the development of realistic novel therapeutic strategies to prevent or reverse the devastating neurotoxic effects of chemotherapy on the (peripheral) nervous system. Cancer 2018;124:2289-98. © 2018 American Cancer Society.

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Section: Targeting Neuronal Mitochondrial Dysfunctionmentioning

confidence: 99%

Section: Targeting Neuronal Mitochondrial Dysfunctionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

Kavelaars

Dougherty

et al. 2018

Cancer

123

111

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“…Analysis of the brain tissue from these mice revealed increased levels of BDNF and synaptic proteins, and enhanced cellular energetics associated with cognitive protection. Similar, restoration of axonal trafficking using antioxidants, by increasing the acetylation of anti-oxidant protein peroxdiredoxin1 by HDAC6 inhibition or by treatment with geniposide, a pharmacologically active component purified from gardenia fruit, resulted in reduced levels of ROS and Ca 2+ , and synaptic protection in multiple cellular and mouse models of AD (Choi et al, 2017; Guo et al, 2013; Lv et al, 2015; Reddy et al, 2012; Yu et al, 2016; Zhang et al, 2016a). Since mitochondrial trafficking inhibition in neurons is not specific to AD (De Vos and Hafezparast, 2017; Morfini et al, 2009; Trushina et al, 2004), the development of therapeutic strategies to restore axonal trafficking could be beneficial for multiple neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

Zhang

Trushin

Christensen

et al. 2018

Neurobiology of Disease

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Inhibition of mitochondrial axonal trafficking by amyloid beta (Aβ) peptides has been implicated in early pathophysiology of Alzheimer’s Disease (AD). Yet, it remains unclear whether the loss of motility inevitably induces the loss of mitochondrial function, and whether restoration of axonal trafficking represents a valid therapeutic target. Moreover, while some investigations identify Aβ oligomers as the culprit of trafficking inhibition, others propose that fibrils play the detrimental role. We have examined the effect of a panel of Aβ peptides with different mutations found in familial AD on mitochondrial motility in primary cortical mouse neurons. Peptides with higher propensity to aggregate inhibit mitochondrial trafficking to a greater extent with fibrils inducing the strongest inhibition. Binding of Aβ peptides to the plasma membrane was sufficient to induce trafficking inhibition where peptides with reduced plasma membrane binding and internalization had lesser effect on mitochondrial motility. We also found that Aβ peptide with Icelandic mutation A673T affects axonal trafficking of mitochondria but has very low rates of plasma membrane binding and internalization in neurons, which could explain its relatively low toxicity. Inhibition of mitochondrial dynamics caused by Aβ peptides or fibrils did not instantly affect mitochondrial bioenergetic and function. Our results support a mechanism where inhibition of axonal trafficking is initiated at the plasma membrane by soluble low molecular weight Aβ species and is exacerbated by fibrils. Since trafficking inhibition does not coincide with the loss of mitochondrial function, restoration of axonal transport could be beneficial at early stages of AD progression. However, strategies designed to block Aβ aggregation or fibril formation alone without ensuring the efficient clearance of soluble Aβ may not be sufficient to alleviate the trafficking phenotype.

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“…[1][2][3] Targets deacetylated by HDAC6 include α-tubulin 4 , HSP90 5 , and cortactin 6 among others. 7,8 HDAC6 is involved in a diverse array of biological processes, including cell motility 9 , immune synapse formation 10 , viral infection 11 , and the degradation of misfolded proteins 12 , and has been associated with diseases. 13 In particular, HDAC6 recruits polyubiquitinated protein aggregates via its ZnF-UBD, and loads misfolded proteins onto dynein for microtubule-guided transport to the lysosome.…”

Section: Introductionmentioning

confidence: 99%

Identification and Structure-Activity Relationship of HDAC6 Zinc-finger Ubiquitin Binding Domain Inhibitors

Freitas

Harding

Franzoni

et al. 2018

Preprint

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HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation, and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of a HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155 are necessary for activity.One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens-up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

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Increased acetylation of Peroxiredoxin1 by HDAC6 inhibition leads to recovery of Aβ-induced impaired axonal transport

Cited by 59 publications

References 54 publications

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

Identification and Structure-Activity Relationship of HDAC6 Zinc-finger Ubiquitin Binding Domain Inhibitors

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