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Tau Phosphorylation—Much More than a Biomarker
Neuron
Previews Tau Phosphorylation—Much More than a Biomarker Sumihiro Maeda1 and Lennart Mucke1,* 1Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2016.10.011
Lasagna-Reeves et al. (2016) demonstrate that preventing the kinase Nuak1 from phosphorylating the microtubule-associated protein tau reduces the level of potentially pathogenic tau species in brain, a novel therapeutic strategy that could help counteract Alzheimer’s disease and several other neurological disorders. Alzheimer’s disease and related disorders cause major disability and are increasing in prevalence in aging populations around the world. Because the etiology of most of these conditions appears to be multifactorial, their effective treatment—impossible at this time—will likely require the development of a multipronged therapeutic approach (Huang and Mucke, 2012). However, this process has been hampered by an incomplete understanding of the causal drivers and disease mechanisms involved. Diverse lines of evidence suggest that tau critically contributes to the pathogenesis of Alzheimer’s disease and many other neurodegenerative disorders collectively referred to as ‘‘tauopathies’’ (Morris et al., 2011; Wang and Mandelkow, 2016). However, this intrinsically disordered protein exists in six main isoforms, undergoes diverse posttranslational modifications, interacts with many other proteins, assumes various conformational states, and can form different types of assemblies, such as oligomers and larger fibrils. The latter gives rise to neurofibrillary tangles, a pathological hallmark of tauopathies. Not too surprisingly, in light of this complexity, it remains uncertain which particular tau species contribute(s) the most to neuronal dysfunction and degeneration in tauopathies and through which mechanism(s). In addition to adverse gain-of-function effects imparted upon tau by amino acid substitutions or other processes that alter its posttranslational modification, folding, or propensity to self-aggregate (Holtzman et al., 2016; Morris et al., 2011; Wang and Mandelkow, 2016), it is possible that physiological functions of tau involved in the regulation of neuronal activity enable or promote network dysfunction in dementia, epilepsy, and related disorders
(Gheyara et al., 2014; Morris et al., 2011). Although loss of tau function has also been hypothesized to play a role in the pathogenesis of neurodegenerative diseases, several lines of experimental evidence make this possibility less likely (DeVos et al., 2013; Li et al., 2014; Morris et al., 2011, 2013). Independent of the precise mechanisms by which tau contributes to the dysfunction and degeneration of brain cells, there is solid experimental evidence that reducing its overall levels or preventing its accumulation in brain could be of therapeutic benefit (DeVos et al., 2013; Holtzman et al., 2016; Li et al., 2014; Min et al., 2015; Morris et al., 2011; Wang and Mandelkow, 2016). Although several strategies have been identified to achieve these objectives (Figure 1) (DeVos et al., 2013; Holtzman et al., 2016; Min et al., 2015; Morris et al., 2011; Wang and Mandelkow, 2016), their efficacy and safety remain to be proven in conclusive clinical trials. It is therefore desirable to identify additional strategies to lower the levels of tau species that may contribute to the pathogenesis of neurological disease. The elegantly designed study by Lasagna-Reeves et al. (2016) published in this issue of Neuron represents an important step in this direction and nicely illustrates that tau phosphorylation is not just a marker of disease, but also a critical regulator of tau metabolism and toxicity. The scientists used two types of RNA interference (RNAi) screens to look for kinases whose inhibition can lower (1) overall tau levels and (2) pathogenic tau effects. In the first screen, which yielded 44 hits, they reduced the expression of every human kinase and kinase-like gene with individual short interfering RNAs (siRNAs) in a human brain-derived
medulloblastoma cell line and measured the impact of this manipulation on the level of a tau:EGFP fusion protein that they overexpressed in these cells. Thus, this screen was designed to look for targets that modulate tau protein levels rather than the expression of the MAPT gene that encodes tau. In the second screen, which yielded 88 hits, they used inducible RNAi alleles targeting the Drosophila kinome in a fruit fly model that overexpresses four-repeat wild-type human tau and develops external eye degeneration. Here, the main readout was amelioration of this phenotype. Among the 16 overlapping hits identified in both screens, the investigators focused on Nuak1, a member of the AMP-activated protein kinase family of serine/ threonine kinases, because even partial reduction of this target robustly lowered tau levels in the human cell line, as well as in the fruit fly model, and effectively suppressed the eye degeneration in the flies. The remainder of the study focused on the further validation of this novel target and on unraveling the mechanisms that link it to tau and tauopathies. Lasagna-Reeves et al. (2016) did not indicate whether other hits that emerged from these interesting screens are being pursued in independent projects. It was also unclear to us whether either of their screens identified the major known tau kinases that phosphorylate tau at multiple sites and that have been shown to modulate tau toxicity, including GSK3b, CDK5, and MARK2 (Morris et al., 2011; Wang and Mandelkow, 2016). Genetic ablation of one Nuak1 allele reduced Nuak1 expression by 50% and partially reduced brain levels of endogenous tau in mice. In a tauopathy model (PS19 mice), this manipulation
Neuron 92, October 19, 2016 ª 2016 Elsevier Inc. 265
Neuron
Previews Anti-tau antisense oligonucleotides
Tau mRNA Tau acetylase inhibitors Other tau kinase inhibitors Tau Protein
? Nuak1
Other tau kinase inhibitors Tau acetylase inhibitors
Anti-tau antibodies Tau aggregation inhibitors
Proteasomal degradation
inhibitors Pathogenic Activity Conformation Assembly Distribution
? Autophagy
?
Autophagy enhancers
Neural Dysfunction Neurodegeneration Figure 1. Inhibition of Nuak1 and Other Investigational Strategies Targeting Tau
lowered brain levels of human tau carrying a mutation (P301S) that causes frontotemporal lobar degeneration and reduced the accumulation of abnormally phosphorylated tau in neurons. Importantly, the investigators also obtained evidence in fly and mouse tauopathy models that reducing Nuak1 levels improves neural functions. Knockdown of the Drosophila homolog of Nuak1 suppressed motor abnormalities in flies overexpressing wild-type human tau, whereas overexpression of Nuak1 worsened this phenotype. In PS19 mice, genetic ablation of one Nuak1 allele reduced memory deficits in the Morris water maze and a contextual fear conditioning paradigm and prevented deficits in long-term potentiation, a form of synaptic plasticity, in the dentate gyrus. It remains to be established whether these beneficial in vivo effects resulted from a moderate reduction in overall tau levels, a more marked reduction of a particularly pathogenic tau species, or an independent mechanism that does not directly affect tau but indirectly counteracts its adverse effects (Figure 1). Taking their validation of Nuak1 into relevant human conditions, LasagnaReeves et al. (2016) demonstrated increased levels of Nuak1 in soluble fractions of postmortem brain tissues from 266 Neuron 92, October 19, 2016
patients with two different tauopathies: frontal cortex from patients with Alzheimer’s disease and pons from patients with progressive supranuclear palsy. In both conditions, Nuak1 immunoreactivity in brain sections colocalized with neurofibrillary tangles. Because of potential species differences and compensatory processes that may occur during early development, but not in adulthood, it is impossible to predict from the data presented by Lasagna-Reeves et al. (2016) whether inhibition of Nuak1 would be safe if implemented in adult humans. During development and early postnatal maturation, Nuak1 has been shown to regulate axon branching and immobilization of mitochondria at nascent presynaptic sites (Courchet et al., 2013). However, young adult Nuak1+/ mice, which presumably had persistent, but partial, reductions in Nuak1 and tau levels since early stages of development, showed no abnormalities in behavior or synaptic plasticity in the paradigms assessed by Lasagna-Reeves et al. (2016). Lasagna-Reeves et al. (2016) used a variety of methods to determine how Nuak1 affects tau, including mass spectrometry, mutagenesis of different serine residues in tau, overexpression of wild-type versus kinase-dead Nuak1 in
neuroblastoma cells, and treatment of cells with a pharmacological inhibitor of Nuak1. Taken together, the results of these mechanistic experiments strongly suggest that Nuak1 phosphorylates tau selectively at Serine356 within the microtubule-binding domain, a process that indirectly promoted the phosphorylation of tau at Thr231 and Ser396/Ser404. As explicitly acknowledged by LasagnaReeves et al. (2016), other groups previously showed that phosphorylation of tau at Ser262 and Ser356 releases tau from microtubules and that phosphorylation of Ser356 promotes phosphorylations of tau at other sites that are associated with tau aggregation. In cell culture experiments, LasagnaReeves et al. (2016) showed that phosphorylation of tau at Serine356—possibly in combination with the cascade of additional posttranslational modifications this event triggers—increases the half-life of tau. Using co-immunoprecipitation assays, they further demonstrate that phosphorylation of Ser356 by Nuak1 disrupts binding of tau to the Hsp70-interacting protein CHIP, which mediates ubiquitination of tau and promotes its proteasomal degradation (Wang and Mandelkow, 2016). These data provide a plausible mechanism for the tau-stabilizing effects of Nuak1, although the existence of additional mechanisms cannot be excluded and may merit further exploration (Figure 1). The precise mechanisms that increase the activity of Nuak1 in different conditions also remain to be defined and—as pointed out by Lasagna-Reeves et al. (2016)—may well be diverse in nature and, depending on the disease process that they form part of, also in consequence. As alluded to by Lasagna-Reeves et al. (2016) in their discussion, the abundance of posttranslational modifications on tau does not necessarily predict the extent of their pathogenic impact. Even a lowabundance modification can have a prominent impact if it triggers more widespread modifications or imparts a unique biological activity upon the resulting tau species. Notably, other kinases, such as PAR-1/MARK, also promote the phosphorylation of Ser356 and the stabilization of tau (Ando et al., 2016; Wang and Mandelkow, 2016), although they phosphorylate additional residues in tau, which
Neuron
Previews appears to be different from Nuak1. Combining inhibitors of these kinases and of other processes that stabilize tau and promote its toxicity, such as tau acetylation (Min et al., 2015; Wang and Mandelkow, 2016), might synergistically maximize their therapeutic effects. The demonstration by Lasagna-Reeves et al. (2016) that partial reduction of tau is safe and can suppress multiple abnormalities in experimental models of neurological diseases is encouraging and consistent with findings obtained by others (DeVos et al., 2013; Gheyara et al., 2014; Holtzman et al., 2016; Min et al., 2015; Morris et al., 2011; Wang and Mandelkow, 2016). It supports the feasibility and potential benefits of antitau strategies and nicely illustrates the diverse entry points for therapeutic intervention that clever screening approaches can uncover in this promising area of drug development.
ACKNOWLEDGMENTS L.M. and S.M. are supported by the Tau Consortium. L.M. is a co-inventor on tau-related patents owned by the Gladstone Institutes. L.M. is also the principal investigator of sponsored research collaborations of the Gladstone Institutes with Bristol-Myers Squibb and with Cure Network Dolby Acceleration Partners.
REFERENCES Ando, K., Oka, M., Ohtake, Y., Hayashishita, M., Shimizu, S., Hisanaga, S., and Iijima, K.M. (2016). Biochem. Biophys. Res. Commun. 478, 929–934. Courchet, J., Lewis, T.L., Jr., Lee, S., Courchet, V., Liou, D.Y., Aizawa, S., and Polleux, F. (2013). Cell 153, 1510–1525. DeVos, S.L., Goncharoff, D.K., Chen, G., Kebodeaux, C.S., Yamada, K., Stewart, F.R., Schuler, D.R., Maloney, S.E., Wozniak, D.F., Rigo, F., et al. (2013). J. Neurosci. 33, 12887–12897. Gheyara, A.L., Ponnusamy, R., Djukic, B., Craft, R.J., Ho, K., Guo, W., Finucane, M.M., Sanchez, P.E., and Mucke, L. (2014). Ann. Neurol. 76, 443–456.
Holtzman, D.M., Carrillo, M.C., Hendrix, J.A., Bain, L.J., Catafau, A.M., Gault, L.M., Goedert, M., Mandelkow, E., Mandelkow, E.M., Miller, D.S., et al. (2016). Alzheimers Dement. http://dx.doi.org/10. 1016/j.jalz.2016.03.018, S1552-5260(16)30019-X. Huang, Y., and Mucke, L. (2012). Cell 148, 1204– 1222. Lasagna-Reeves, C.A., de Haro, M., Hao, S., Park, J., Rousseaux, M.W.C., Al-Ramahi, I., Jafar-Nejad, P., Vilanova-Velez, L., See, L., De Maio, A., et al. (2016). Neuron 92, this issue, 407–418. Li, Z., Hall, A.M., Kelinske, M., and Roberson, E.D. (2014). Neurobiol. Aging 35, 2617–2624. Min, S.W., Chen, X., Tracy, T.E., Li, Y., Zhou, Y., Wang, C., Shirakawa, K., Minami, S.S., Defensor, E., Mok, S.A., et al. (2015). Nat. Med. 21, 1154– 1162. Morris, M., Maeda, S., Vossel, K., and Mucke, L. (2011). Neuron 70, 410–426. Morris, M., Hamto, P., Adame, A., Devidze, N., Masliah, E., and Mucke, L. (2013). Neurobiol. Aging 34, 1523–1529. Wang, Y., and Mandelkow, E. (2016). Nat. Rev. Neurosci. 17, 5–21.
Synaptic Suppression of Axon Regeneration Jessica M. Meves1 and Binhai Zheng1,* 1Neurosciences Graduate Program and Department of Neurosciences, University of California San Diego, School of Medicine, 9500 Gilman Drive, MC 0691, La Jolla, CA 92093, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2016.10.012
In this issue of Neuron, Tedeschi et al. (2016) describe the voltage-gated calcium channel subunit alpha2delta2 as a developmental switch from axon elongation to synapse formation and transmission that doubles as a suppressor of axon regeneration, providing a molecular clue for the synaptic stabilization hypothesis of CNS regeneration failure. A key question in the field of neural regeneration research is why axons in the adult mammalian CNS fail to regenerate after injury. In particular, why are the mechanisms enabling axon growth during development no longer operating after injury in the adult CNS? Both a loss of neuronintrinsic growth promoters and a gain of extrinsic (e.g., glia-derived) growth inhibitors in the injured adult CNS have been extensively investigated to explain this regeneration failure (Chen and Zheng, 2014). What remains less clear is whether neurons gain intrinsic properties at a later
developmental stage that hinder axonal growth. Could such a ‘‘maturation’’ property also operate in adult neurons to suppress axon regeneration after injury? The study by Tedeschi et al. (2016) provides evidence that this may indeed be the case by identifying a molecular link between neuronal maturation and axon regeneration. Tedeschi et al. (2016) hypothesized that the developmental switch from an axon growth phase to a synaptic connectivity or transmission phase marks the activation of an axon growth suppressing mech-
anism that could impair regeneration after injury in the adult CNS. Accordingly, genes that are activated during this developmental switch would correlate negatively with the growth competence of adult neurons. They evaluated the transcriptome profiles of dorsal root ganglion (DRG) sensory neurons with varying degrees of axon growth competence in three different experimental paradigms: (1) DRG neurons from embryonic day 12.5 and 17.5 (E12.5 and E17.5) mouse embryos representing, respectively, an axon growth phase and a phase when
Neuron 92, October 19, 2016 ª 2016 Elsevier Inc. 267
Previews Tau Phosphorylation—Much More than a Biomarker Sumihiro Maeda1 and Lennart Mucke1,* 1Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2016.10.011
Lasagna-Reeves et al. (2016) demonstrate that preventing the kinase Nuak1 from phosphorylating the microtubule-associated protein tau reduces the level of potentially pathogenic tau species in brain, a novel therapeutic strategy that could help counteract Alzheimer’s disease and several other neurological disorders. Alzheimer’s disease and related disorders cause major disability and are increasing in prevalence in aging populations around the world. Because the etiology of most of these conditions appears to be multifactorial, their effective treatment—impossible at this time—will likely require the development of a multipronged therapeutic approach (Huang and Mucke, 2012). However, this process has been hampered by an incomplete understanding of the causal drivers and disease mechanisms involved. Diverse lines of evidence suggest that tau critically contributes to the pathogenesis of Alzheimer’s disease and many other neurodegenerative disorders collectively referred to as ‘‘tauopathies’’ (Morris et al., 2011; Wang and Mandelkow, 2016). However, this intrinsically disordered protein exists in six main isoforms, undergoes diverse posttranslational modifications, interacts with many other proteins, assumes various conformational states, and can form different types of assemblies, such as oligomers and larger fibrils. The latter gives rise to neurofibrillary tangles, a pathological hallmark of tauopathies. Not too surprisingly, in light of this complexity, it remains uncertain which particular tau species contribute(s) the most to neuronal dysfunction and degeneration in tauopathies and through which mechanism(s). In addition to adverse gain-of-function effects imparted upon tau by amino acid substitutions or other processes that alter its posttranslational modification, folding, or propensity to self-aggregate (Holtzman et al., 2016; Morris et al., 2011; Wang and Mandelkow, 2016), it is possible that physiological functions of tau involved in the regulation of neuronal activity enable or promote network dysfunction in dementia, epilepsy, and related disorders
(Gheyara et al., 2014; Morris et al., 2011). Although loss of tau function has also been hypothesized to play a role in the pathogenesis of neurodegenerative diseases, several lines of experimental evidence make this possibility less likely (DeVos et al., 2013; Li et al., 2014; Morris et al., 2011, 2013). Independent of the precise mechanisms by which tau contributes to the dysfunction and degeneration of brain cells, there is solid experimental evidence that reducing its overall levels or preventing its accumulation in brain could be of therapeutic benefit (DeVos et al., 2013; Holtzman et al., 2016; Li et al., 2014; Min et al., 2015; Morris et al., 2011; Wang and Mandelkow, 2016). Although several strategies have been identified to achieve these objectives (Figure 1) (DeVos et al., 2013; Holtzman et al., 2016; Min et al., 2015; Morris et al., 2011; Wang and Mandelkow, 2016), their efficacy and safety remain to be proven in conclusive clinical trials. It is therefore desirable to identify additional strategies to lower the levels of tau species that may contribute to the pathogenesis of neurological disease. The elegantly designed study by Lasagna-Reeves et al. (2016) published in this issue of Neuron represents an important step in this direction and nicely illustrates that tau phosphorylation is not just a marker of disease, but also a critical regulator of tau metabolism and toxicity. The scientists used two types of RNA interference (RNAi) screens to look for kinases whose inhibition can lower (1) overall tau levels and (2) pathogenic tau effects. In the first screen, which yielded 44 hits, they reduced the expression of every human kinase and kinase-like gene with individual short interfering RNAs (siRNAs) in a human brain-derived
medulloblastoma cell line and measured the impact of this manipulation on the level of a tau:EGFP fusion protein that they overexpressed in these cells. Thus, this screen was designed to look for targets that modulate tau protein levels rather than the expression of the MAPT gene that encodes tau. In the second screen, which yielded 88 hits, they used inducible RNAi alleles targeting the Drosophila kinome in a fruit fly model that overexpresses four-repeat wild-type human tau and develops external eye degeneration. Here, the main readout was amelioration of this phenotype. Among the 16 overlapping hits identified in both screens, the investigators focused on Nuak1, a member of the AMP-activated protein kinase family of serine/ threonine kinases, because even partial reduction of this target robustly lowered tau levels in the human cell line, as well as in the fruit fly model, and effectively suppressed the eye degeneration in the flies. The remainder of the study focused on the further validation of this novel target and on unraveling the mechanisms that link it to tau and tauopathies. Lasagna-Reeves et al. (2016) did not indicate whether other hits that emerged from these interesting screens are being pursued in independent projects. It was also unclear to us whether either of their screens identified the major known tau kinases that phosphorylate tau at multiple sites and that have been shown to modulate tau toxicity, including GSK3b, CDK5, and MARK2 (Morris et al., 2011; Wang and Mandelkow, 2016). Genetic ablation of one Nuak1 allele reduced Nuak1 expression by 50% and partially reduced brain levels of endogenous tau in mice. In a tauopathy model (PS19 mice), this manipulation
Neuron 92, October 19, 2016 ª 2016 Elsevier Inc. 265
Neuron
Previews Anti-tau antisense oligonucleotides
Tau mRNA Tau acetylase inhibitors Other tau kinase inhibitors Tau Protein
? Nuak1
Other tau kinase inhibitors Tau acetylase inhibitors
Anti-tau antibodies Tau aggregation inhibitors
Proteasomal degradation
inhibitors Pathogenic Activity Conformation Assembly Distribution
? Autophagy
?
Autophagy enhancers
Neural Dysfunction Neurodegeneration Figure 1. Inhibition of Nuak1 and Other Investigational Strategies Targeting Tau
lowered brain levels of human tau carrying a mutation (P301S) that causes frontotemporal lobar degeneration and reduced the accumulation of abnormally phosphorylated tau in neurons. Importantly, the investigators also obtained evidence in fly and mouse tauopathy models that reducing Nuak1 levels improves neural functions. Knockdown of the Drosophila homolog of Nuak1 suppressed motor abnormalities in flies overexpressing wild-type human tau, whereas overexpression of Nuak1 worsened this phenotype. In PS19 mice, genetic ablation of one Nuak1 allele reduced memory deficits in the Morris water maze and a contextual fear conditioning paradigm and prevented deficits in long-term potentiation, a form of synaptic plasticity, in the dentate gyrus. It remains to be established whether these beneficial in vivo effects resulted from a moderate reduction in overall tau levels, a more marked reduction of a particularly pathogenic tau species, or an independent mechanism that does not directly affect tau but indirectly counteracts its adverse effects (Figure 1). Taking their validation of Nuak1 into relevant human conditions, LasagnaReeves et al. (2016) demonstrated increased levels of Nuak1 in soluble fractions of postmortem brain tissues from 266 Neuron 92, October 19, 2016
patients with two different tauopathies: frontal cortex from patients with Alzheimer’s disease and pons from patients with progressive supranuclear palsy. In both conditions, Nuak1 immunoreactivity in brain sections colocalized with neurofibrillary tangles. Because of potential species differences and compensatory processes that may occur during early development, but not in adulthood, it is impossible to predict from the data presented by Lasagna-Reeves et al. (2016) whether inhibition of Nuak1 would be safe if implemented in adult humans. During development and early postnatal maturation, Nuak1 has been shown to regulate axon branching and immobilization of mitochondria at nascent presynaptic sites (Courchet et al., 2013). However, young adult Nuak1+/ mice, which presumably had persistent, but partial, reductions in Nuak1 and tau levels since early stages of development, showed no abnormalities in behavior or synaptic plasticity in the paradigms assessed by Lasagna-Reeves et al. (2016). Lasagna-Reeves et al. (2016) used a variety of methods to determine how Nuak1 affects tau, including mass spectrometry, mutagenesis of different serine residues in tau, overexpression of wild-type versus kinase-dead Nuak1 in
neuroblastoma cells, and treatment of cells with a pharmacological inhibitor of Nuak1. Taken together, the results of these mechanistic experiments strongly suggest that Nuak1 phosphorylates tau selectively at Serine356 within the microtubule-binding domain, a process that indirectly promoted the phosphorylation of tau at Thr231 and Ser396/Ser404. As explicitly acknowledged by LasagnaReeves et al. (2016), other groups previously showed that phosphorylation of tau at Ser262 and Ser356 releases tau from microtubules and that phosphorylation of Ser356 promotes phosphorylations of tau at other sites that are associated with tau aggregation. In cell culture experiments, LasagnaReeves et al. (2016) showed that phosphorylation of tau at Serine356—possibly in combination with the cascade of additional posttranslational modifications this event triggers—increases the half-life of tau. Using co-immunoprecipitation assays, they further demonstrate that phosphorylation of Ser356 by Nuak1 disrupts binding of tau to the Hsp70-interacting protein CHIP, which mediates ubiquitination of tau and promotes its proteasomal degradation (Wang and Mandelkow, 2016). These data provide a plausible mechanism for the tau-stabilizing effects of Nuak1, although the existence of additional mechanisms cannot be excluded and may merit further exploration (Figure 1). The precise mechanisms that increase the activity of Nuak1 in different conditions also remain to be defined and—as pointed out by Lasagna-Reeves et al. (2016)—may well be diverse in nature and, depending on the disease process that they form part of, also in consequence. As alluded to by Lasagna-Reeves et al. (2016) in their discussion, the abundance of posttranslational modifications on tau does not necessarily predict the extent of their pathogenic impact. Even a lowabundance modification can have a prominent impact if it triggers more widespread modifications or imparts a unique biological activity upon the resulting tau species. Notably, other kinases, such as PAR-1/MARK, also promote the phosphorylation of Ser356 and the stabilization of tau (Ando et al., 2016; Wang and Mandelkow, 2016), although they phosphorylate additional residues in tau, which
Neuron
Previews appears to be different from Nuak1. Combining inhibitors of these kinases and of other processes that stabilize tau and promote its toxicity, such as tau acetylation (Min et al., 2015; Wang and Mandelkow, 2016), might synergistically maximize their therapeutic effects. The demonstration by Lasagna-Reeves et al. (2016) that partial reduction of tau is safe and can suppress multiple abnormalities in experimental models of neurological diseases is encouraging and consistent with findings obtained by others (DeVos et al., 2013; Gheyara et al., 2014; Holtzman et al., 2016; Min et al., 2015; Morris et al., 2011; Wang and Mandelkow, 2016). It supports the feasibility and potential benefits of antitau strategies and nicely illustrates the diverse entry points for therapeutic intervention that clever screening approaches can uncover in this promising area of drug development.
ACKNOWLEDGMENTS L.M. and S.M. are supported by the Tau Consortium. L.M. is a co-inventor on tau-related patents owned by the Gladstone Institutes. L.M. is also the principal investigator of sponsored research collaborations of the Gladstone Institutes with Bristol-Myers Squibb and with Cure Network Dolby Acceleration Partners.
REFERENCES Ando, K., Oka, M., Ohtake, Y., Hayashishita, M., Shimizu, S., Hisanaga, S., and Iijima, K.M. (2016). Biochem. Biophys. Res. Commun. 478, 929–934. Courchet, J., Lewis, T.L., Jr., Lee, S., Courchet, V., Liou, D.Y., Aizawa, S., and Polleux, F. (2013). Cell 153, 1510–1525. DeVos, S.L., Goncharoff, D.K., Chen, G., Kebodeaux, C.S., Yamada, K., Stewart, F.R., Schuler, D.R., Maloney, S.E., Wozniak, D.F., Rigo, F., et al. (2013). J. Neurosci. 33, 12887–12897. Gheyara, A.L., Ponnusamy, R., Djukic, B., Craft, R.J., Ho, K., Guo, W., Finucane, M.M., Sanchez, P.E., and Mucke, L. (2014). Ann. Neurol. 76, 443–456.
Holtzman, D.M., Carrillo, M.C., Hendrix, J.A., Bain, L.J., Catafau, A.M., Gault, L.M., Goedert, M., Mandelkow, E., Mandelkow, E.M., Miller, D.S., et al. (2016). Alzheimers Dement. http://dx.doi.org/10. 1016/j.jalz.2016.03.018, S1552-5260(16)30019-X. Huang, Y., and Mucke, L. (2012). Cell 148, 1204– 1222. Lasagna-Reeves, C.A., de Haro, M., Hao, S., Park, J., Rousseaux, M.W.C., Al-Ramahi, I., Jafar-Nejad, P., Vilanova-Velez, L., See, L., De Maio, A., et al. (2016). Neuron 92, this issue, 407–418. Li, Z., Hall, A.M., Kelinske, M., and Roberson, E.D. (2014). Neurobiol. Aging 35, 2617–2624. Min, S.W., Chen, X., Tracy, T.E., Li, Y., Zhou, Y., Wang, C., Shirakawa, K., Minami, S.S., Defensor, E., Mok, S.A., et al. (2015). Nat. Med. 21, 1154– 1162. Morris, M., Maeda, S., Vossel, K., and Mucke, L. (2011). Neuron 70, 410–426. Morris, M., Hamto, P., Adame, A., Devidze, N., Masliah, E., and Mucke, L. (2013). Neurobiol. Aging 34, 1523–1529. Wang, Y., and Mandelkow, E. (2016). Nat. Rev. Neurosci. 17, 5–21.
Synaptic Suppression of Axon Regeneration Jessica M. Meves1 and Binhai Zheng1,* 1Neurosciences Graduate Program and Department of Neurosciences, University of California San Diego, School of Medicine, 9500 Gilman Drive, MC 0691, La Jolla, CA 92093, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2016.10.012
In this issue of Neuron, Tedeschi et al. (2016) describe the voltage-gated calcium channel subunit alpha2delta2 as a developmental switch from axon elongation to synapse formation and transmission that doubles as a suppressor of axon regeneration, providing a molecular clue for the synaptic stabilization hypothesis of CNS regeneration failure. A key question in the field of neural regeneration research is why axons in the adult mammalian CNS fail to regenerate after injury. In particular, why are the mechanisms enabling axon growth during development no longer operating after injury in the adult CNS? Both a loss of neuronintrinsic growth promoters and a gain of extrinsic (e.g., glia-derived) growth inhibitors in the injured adult CNS have been extensively investigated to explain this regeneration failure (Chen and Zheng, 2014). What remains less clear is whether neurons gain intrinsic properties at a later
developmental stage that hinder axonal growth. Could such a ‘‘maturation’’ property also operate in adult neurons to suppress axon regeneration after injury? The study by Tedeschi et al. (2016) provides evidence that this may indeed be the case by identifying a molecular link between neuronal maturation and axon regeneration. Tedeschi et al. (2016) hypothesized that the developmental switch from an axon growth phase to a synaptic connectivity or transmission phase marks the activation of an axon growth suppressing mech-
anism that could impair regeneration after injury in the adult CNS. Accordingly, genes that are activated during this developmental switch would correlate negatively with the growth competence of adult neurons. They evaluated the transcriptome profiles of dorsal root ganglion (DRG) sensory neurons with varying degrees of axon growth competence in three different experimental paradigms: (1) DRG neurons from embryonic day 12.5 and 17.5 (E12.5 and E17.5) mouse embryos representing, respectively, an axon growth phase and a phase when
Neuron 92, October 19, 2016 ª 2016 Elsevier Inc. 267