Deregulation of HDAC1 by p25/Cdk5 in Neurotoxicity

Kim, Do-Hoon; Frank, Christopher L.; Dobbin, Matthew M.; Tsunemoto, Rachel; Tu, Weihong; Peng, Peter L.; Guan, Ji‐Song; Lee, Byung‐Hoon; Moy, Lily Y.; Giusti, Paola; Broodie, Nisha; Mazitschek, Ralph; Delalle, Ivana; Haggarty, Stephen J.; Neve, Rachael L.; Lu, Youming; Tsai, Li‐Huei

doi:10.1016/j.neuron.2008.10.015

Cited by 260 publications

(300 citation statements)

References 66 publications

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“…8C). We also observed robust astrocytosis (using GFAP staining) and induction of markers of cell cycle re-entry (PCNA) in the same area, which are consistent with previously published findings (Kim et al, 2008), and indicates Foxo3 is correlated with other early pathological changes induced by p25 overexpression. Thus, these data strongly confirm the results obtained from HT22 and primary neurons, and suggest that the activation of Cdk5 in p25-inducible mice induces the expression and nuclear localization of Foxo3 levels.…”

Section: Foxo3 Signaling In Mature Primary Cortical Neuronssupporting

confidence: 92%

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Shi

Viccaro

Lee

et al. 2016

Journal of Cell Science

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Deregulated Cdk5 causes neurotoxic amyloid beta peptide (Aβ) processing and cell death, two hallmarks of Alzheimer's disease, through the Foxo3 transcriptional factor in hippocampal cells, primary neurons and an Alzheimer's disease mouse model. Using an innovative chemical genetic screen, we identified Foxo3 as a direct substrate of Cdk5 in brain lysates. Cdk5 directly phosphorylates Foxo3, which increased its levels and nuclear translocation. Nuclear Foxo3 initially rescued cells from ensuing oxidative stress by upregulating MnSOD (also known as SOD2). However, following prolonged exposure, Foxo3 upregulated Bim (also known as BCL2L11) and FasL (also known as FASLG) causing cell death. Active Foxo3 also increased Aβ(1-42) levels in a phosphorylationdependent manner. These events were completely inhibited either by expressing phosphorylation-resistant Foxo3 or by depleting Cdk5 or Foxo3, highlighting a key role for Cdk5 in regulating Foxo3. These results were confirmed in an Alzheimer's disease mouse model, which exhibited increased levels and nuclear localization of Foxo3 in hippocampal neurons, which preceded neurodegeneration and Aβ plaque formation, indicating this phenomenon is an early event in Alzheimer's disease pathogenesis. Collectively, these results show that Cdk5-mediated phospho-regulation of Foxo3 can activate several genes that promote neuronal death and aberrant Aβ processing, thereby contributing to the progression of neurodegenerative pathologies.

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Section: Foxo3 Signaling In Mature Primary Cortical Neuronssupporting

confidence: 92%

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Shi

Viccaro

Lee

et al. 2016

Journal of Cell Science

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“…Although most proteins we examined were not abnormally expressed (Methods), two were. Proliferating cell nuclear antigen (PCNA), a protein associated with mitotically active cells, is found in neuronal nuclei of neurodegenerative diseased brains (27,28). It was intensely present in small, glial-sized nuclei of all brain sections, as expected.…”

Section: Resultssupporting

confidence: 58%

“…Adult neurons are nondividing, and H2A.X is associated with the degenerative process (27,28). Tiny punctate nuclear deposits were present throughout WT brains (Fig.…”

Section: Resultsmentioning

confidence: 93%

Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases

Jackson

Borkowski

Watson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In man, mutations in different regions of the prion protein (PrP) are associated with infectious neurodegenerative diseases that have remarkably different clinical signs and neuropathological lesions. To explore the roots of this phenomenon, we created a knock-in mouse model carrying the mutation associated with one of these diseases [Creutzfeldt-Jakob disease (CJD)] that was exactly analogous to a previous knock-in model of a different prion disease [fatal familial insomnia (FFI)]. Together with the WT parent, this created an allelic series of three lines, each expressing the same protein with a single amino acid difference, and with all native regulatory elements intact. The previously described FFI mice develop neuronal loss and intense reactive gliosis in the thalamus, as seen in humans with FFI. In contrast, CJD mice had the hallmark features of CJD, spongiosis and proteinase K-resistant PrP aggregates, initially developing in the hippocampus and cerebellum but absent from the thalamus. A molecular transmission barrier protected the mice from any infectious prion agents that might have been present in our mouse facility and allowed us to conclude that the diseases occurred spontaneously. Importantly, both models created agents that caused a transmissible neurodegenerative disease in WT mice. We conclude that single codon differences in a single gene in an otherwise normal genome can cause remarkably different neurodegenerative diseases and are sufficient to create distinct protein-based infectious elements.neurodegeneration | protein aggregation | protein misfolding | transgenic mice

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“…Both HDACs are expressed in adult mouse hippocampus, where HDAC1 is expressed in glia and neural progenitor cells, and HDAC2 is expressed in neurons and neural progenitors (16). HDAC1 regulates cell proliferation and differentiation and is neuroprotective in mouse forebrain (17). HDAC2 negatively modulates hippocampal memory and synaptic plasticity in adult mice (15).…”

Section: Resultsmentioning

confidence: 99%

“…This issue will need to be addressed in future studies. Although recent work shows no role for HDAC1 in hippocampal memory (15), HDAC1 is neuroprotective in forebrain neurons (17), and E 2 -induced alterations in HDAC1 may be involved in the neuroprotective effects of E 2 on hippocampal neurons (25). Understanding whether HDAC1 or HDAC2 modulate E 2 -induced increases in H3 acetylation and object recognition could be of clinical significance, given that nearly a dozen HDAC inhibitors are already in clinical trials for the treatment of various cancers (26).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic alterations regulate estradiol-induced enhancement of memory consolidation

Zhao¹,

Liu²,

Frick

2010

Proc. Natl. Acad. Sci. U.S.A.

194

325

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The involvement of epigenetic alterations in mediating effects of estrogens on memory is unknown. The present study determined whether histone acetylation and DNA methylation are critical for the potent estrogen 17β-estradiol (E 2 ) to enhance object recognition memory. We show that dorsal hippocampal E 2 infusion increases acetylation of dorsal hippocampal histone H3, but not H4-an effect blocked by dorsal hippocampal inhibition of ERK activation. Further, intrahippocampal inhibition of ERK activation or DNA methyltransferase (DNMT) activity blocked the memory-enhancing effects of E 2 . Consistent with these effects, E 2 decreased levels of HDAC2 protein and increased DNMT expression in the dorsal hippocampus. These findings provide evidence that the beneficial effects of E 2 on memory consolidation are associated with epigenetic alterations, and suggest these can be triggered by dorsal hippocampal ERK signaling.T he specific molecular mechanisms underlying the mnemonic effects of estrogens remain largely unknown. We recently showed that activation of the extracellular signal-regulated kinase/ mitogen-activated protein kinase (ERK/MAPK) signaling cascade in the dorsal hippocampus is necessary for the potent estrogen 17β-estradiol (E 2 ) to enhance novel object recognition in young female mice (1). In this study, i.p. injection of E 2 immediately after object recognition training significantly enhanced long-term memory and increased p42 ERK phosphorylation in the dorsal hippocampus; both effects were blocked by inhibiting MAPK kinase (MEK), the exclusive upstream activator of ERK (1).Activated ERK can promote the expression of genes associated with learning and memory, in part, by activating transcription factors such as CREB (2, 3). ERK may also increase gene expression by regulating epigenetic mechanisms necessary for memory formation, such as histone acetylation and DNA methylation; recent findings suggest that ERK activation influences both processes (4-7). Thus, these mechanisms may also play a role in estrogenic modulation of memory. DNA is wound around a core of eight histone proteins, two each of histones H2A, H2B, H3, and H4. Acetylation of lysine residues on histone tails relaxes the bond between histones and DNA, allowing transcriptional access. Histone acetylation is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs) (8). Genetic disruption of HAT activity impairs hippocampal memory, and these deficits are rescued by HDAC inhibitors (9). HDAC inhibitors such as trichostatin A (TSA) prevent deacetylation of histones H3 and H4, and enhance induction of hippocampal long-term potentiation (LTP), long-term contextual fear conditioning (CFC), and novel object recognition (4, 10-12). Acetylation of hippocampal histone H3, but not H4, is increased following ERK activation or CFC (4, 5), and ERK activation is necessary for other protein kinases (e.g., protein kinase C, PKC) to increase hippocampal H3 acetylation (4). Collectively, these data suggest that histone acetylation regul...

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Deregulation of HDAC1 by p25/Cdk5 in Neurotoxicity

Cited by 260 publications

References 66 publications

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases

Epigenetic alterations regulate estradiol-induced enhancement of memory consolidation

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