Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome

Okur, Mustafa Nazir; Mao, Beatrice; Kimura, Risako; Haraczy, Scott J.; Fitzgerald, Tracy S.; Edwards-Hollingsworth, Kamren; Tian, Jane; Osmani, Wasif; Croteau, Deborah L.; Kelley, Matthew W.; Bohr, Vilhelm A.

doi:10.1038/s41514-019-0040-z

Cited by 48 publications

(59 citation statements)

References 39 publications

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“…To understand the similar pathology in all CS models, we also included GO terms from the cerebellum of CSB mutant mice and their controls from a previously published study [4]. CSB mice recapitulate the features of small body size, hearing loss, retinal degeneration [31-33]. In addition to these features, we showed the presence of reduced muscle strength in old CSB mutant mice (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 92%

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Okur

Fang

Fivenson

et al. 2020

Preprint

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16Background: Cockayne syndrome (CS) is a rare premature aging disease, most 17 commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS 18 patients display cachectic dwarfism and severe neurological manifestations and have 19 an average life expectancy of 12 years. The CS proteins are involved in transcription 20 and DNA repair, with the latter including transcription-coupled nucleotide excision repair 21 (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which 22 likely contributes to the severe premature aging phenotype of this disease. While 23 48 proteins. CSA [5, 6] and CSB [7] are DNA damage response proteins that are involved 49 in transcription-coupled nucleotide excision repair (TC-NER), as well as both nuclear 50 and mitochondrial base excision repair (BER) [8]. NER is a versatile DNA repair 51 pathway as it is responsible for the removal of a wide range of DNA adducts. CSA and 52 CSB are also important for transcription recovery after DNA damage [9][10][11]. Various 53 studies have shown that CSB plays a considerable role in transcription, and likely is a 54 transcription factor [12][13][14][15]. 55 56 Similar to other DNA repair-defective premature aging diseases, such as xeroderma 57 pigmentosum (XP) [16], ataxia-telangiectasia (AT) [17], and Werner syndrome (WS) 58[18], mitochondrial dysfunction is implicated in many CS phenotypes [3, 4, 19]. The 59 mechanisms of mitochondrial dysfunction underlying CS remain unclear but may involve 60 the impairment of the NAD + (nicotinamide adenine dinucleotide, oxidized)-mitophagy 61 axis [19][20][21][22]. NAD + is a fundamental molecule in cellular energy metabolism and 62 signaling pathways and is essential for adaptive responses of cells to bioenergetics and 63 oxidative stress; accordingly, there is an age-dependent depletion of cellular NAD + , 64 suggesting NAD + depletion as a major driver of both pathological and biological aging 65[23]. Many molecular mechanisms are involved in the multi-faceted effects of NAD + on 66 longevity and healthspan, including the induction of mitophagy, a cellular self-67 recognition, engulfment, degradation, and recycling of damaged and superfluous 68 mitochondria [24][25][26]. In CS, the accumulation of unrepaired DNA damage may lead to 69 to those observed in CS patients. After the selection of terms with p-values lower than 130 0.05 and an absolute value pathway Z-Score cut-off of 2.0, the remaining 39 GO terms 131and their respective Z-Scores were sorted by clustering in Fig 1b. Surprisingly, csa-1 132 and csb-1 worms had opposite pathway changes for a majority of the terms. Throughout 133 the dataset, csa-1;csb-1 worms partitioned more with csa-1 than csb-1 worms, 134suggesting that csa-1 drives the double mutant phenotype. However, there was a 135 shortlist of terms, including lysosome, where the csa-1;csb-1 worms segregated with 136 csb-1 worms. Other terms in this group included histidine catabolic process to glutamate 137 and formamide, oxidoreductase activity, an...

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Section: Resultsmentioning

confidence: 92%

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Okur

Fang

Fivenson

et al. 2020

Preprint

Self Cite

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“…The Nnt protein catalyses the generation of NADPH from NADH. Differences in NADH levels have been recently proposed to modulate ribbon dynamics possibly by direct binding to RIBEYE 82,83 that contains an NADH-binding site 14 . Therefore, some differential effects might also be caused by alterations in NADH/NADPH metabolisms in the two different C57BL/6 sub-strains that might modulate ribbon dynamics.…”

Section: Discussionmentioning

confidence: 99%

Synaptic ribbons foster active zone stability and illumination-dependent active zone enrichment of RIM2 and Cav1.4 in photoreceptor synapses

Dembla

Maxeiner

et al. 2020

Sci Rep

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Rod photoreceptor synapses use large, ribbon-type active zones for continuous synaptic transmission during light and dark. Since ribbons are physically connected to the active zones, we asked whether illumination-dependent changes of ribbons influence Cav1.4/RIM2 protein clusters at the active zone and whether these illumination-dependent effects at the active zone require the presence of the synaptic ribbon. We found that synaptic ribbon length and the length of presynaptic Cav1.4/RIM2 clusters are tightly correlated. Dark-adaptation did not change the number of ribbons and active zone puncta. However, mean ribbon length and length of presynaptic Cav1.4/RIM2 clusters increased significantly during dark-adaptation when tonic exocytosis is highest. In the present study, we identified by the analyses of synaptic ribbon-deficient RIBEYE knockout mice that synaptic ribbons are (1) needed to stabilize Cav1.4/RIM2 at rod photoreceptor active zones and (2) are required for the darkness-induced active zone enrichment of Cav1.4/RIM2. These data propose a role of the ribbon in active zone stabilization and suggest a homeostatic function of the ribbon in illumination-dependent active zone remodeling. The active zone of the presynaptic terminal controls central aspects of presynaptic communication 1,2. It is a protein-rich, electron-dense specialization of the plasma membrane at which synaptic vesicle fusion preferentially occurs. The active zone is strongly enriched in voltage-gated Cav-channels and active zone proteins, e.g. RIM-proteins, that attach the vesicle fusion machinery in close proximity to the Cav-channels for tight coupling creating rapidly reacting nanodomains 1,3-9. Ribbon synapses are continuously active chemical synapses with specialized active zones that are considered to promote both fast, transient and slow, continuous synaptic vesicle exocytosis 10,11. The active zone of ribbon synapses is extended by large electron-dense structures, synaptic ribbons, that recruit additional vesicles to the active zone. The basal row of ribbon-associated vesicles is positioned close to the Cav-channels and represents the fastest releasable vesicle pool 12 ideally suited to signal the onset of a stimulus. Synaptic vesicles tethered to the ribbon body, i.e. in some distance from the active zone, are considered to replenish empty release sites at the active zone with slower release kinetics providing information predominantly about the length of the stimulus 12,13. The main structural component of ribbons is the ribbon-specific protein RIBEYE 14,15. Photoreceptor ribbon synapses are the first synapses in the visual system at which light signals are transmitted to the inner retina. Light induces hyperpolarization of photoreceptors and a decrease of exocytosis at the synapse 16. Rod synapses represent the majority of photoreceptor synapses in the mouse retina and are built in a morphologically fairly uniform manner. They use a single large active zone with a single large ribbon. In EM cross-sections, rod ribbons typically ap...

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“…We speculate that decreased binding of NQO1 to microtubules could either enable access of acetyltransferases to acetyl α-tubulin K 40 or result in inhibition of the activity of deacetylases at that specific site in the microtubule lumen. In support of these data, significant differences in the in-vivo acetylome have also been observed in mice after genetic manipulation of NQO1 levels [ 44 ].…”

Section: Discussionmentioning

confidence: 71%

A redox-mediated conformational change in NQO1 controls binding to microtubules and α-tubulin acetylation

et al. 2021

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The localization of NQO1 near acetylated microtubules has led to the hypothesis that NQO1 may work in concert with the NAD + -dependent deacetylase SIRT2 to regulate acetyl α-tubulin (K 40 ) levels on microtubules. NQO1 catalyzes the oxidation of NADH to NAD + and may supplement levels of NAD + near microtubules to aid SIRT2 deacetylase activity. While HDAC6 has been shown to regulate the majority of microtubule acetylation at K 40 , SIRT2 is also known to modulate microtubule acetylation (K 40 ) in the perinuclear region. In this study we examined the potential roles NQO1 may play in modulating acetyl α-tubulin levels. Knock-out or knock-down of NQO1 or SIRT2 did not change the levels of acetyl α-tubulin in 16HBE human bronchial epithelial cells and 3T3-L1 fibroblasts; however, treatment with a mechanism-based inhibitor of NQO1 (MI2321) led to a short-lived temporal increase in acetyl α-tubulin levels in both cell lines without impacting the intracellular pools of NADH or NAD + . Inactivation of NQO1 by MI2321 resulted in lower levels of NQO1 immunostaining on microtubules, consistent with redox-dependent changes in NQO1 conformation as evidenced by the use of redox-specific, anti-NQO1 antibodies in immunoprecipitation studies. Given the highly dynamic nature of acetylation-deacetylation reactions at α-tubulin K 40 and the crowded protein environment surrounding this site, disruption in the binding of NQO1 to microtubules may temporally disturb the physical interactions of enzymes responsible for maintaining the microtubule acetylome.

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Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome

Cited by 48 publications

References 39 publications

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Synaptic ribbons foster active zone stability and illumination-dependent active zone enrichment of RIM2 and Cav1.4 in photoreceptor synapses

A redox-mediated conformational change in NQO1 controls binding to microtubules and α-tubulin acetylation

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Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome

Cited by 48 publications

References 39 publications

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+signaling

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+signaling

Synaptic ribbons foster active zone stability and illumination-dependent active zone enrichment of RIM2 and Cav1.4 in photoreceptor synapses

A redox-mediated conformational change in NQO1 controls binding to microtubules and α-tubulin acetylation

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Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling