TNIK influence the effects of antipsychotics on Wnt/β-catenin signaling pathway

Yuan, Ruixue; Li, Yaojing; Fu, Yingmei; Ning, Ailing; Wang, Dongxiang; Zhang, Ran; Yu, Shunying; Xu, Qingqing

doi:10.1007/s00213-021-05943-3

Cited by 6 publications

(3 citation statements)

References 46 publications

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“…When crossed with the APP/PS1 line, Lrp6 KO mice demonstrated enhanced Aβ production leading to inhibition of Wnt signaling, a finding also seen in Alzheimer brains [ 55 ]. Interestingly, clozapine reduced β-catenin and TCF-4 (encoded by TCF7L2), an effect mediated through down-regulation of TNIK (Traf2- and Nck-interacting kinase) [ 90 ]. TNIK is up-regulated by either Apoer2-ICD (Fig.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the hippocampal translatome by Apoer2-ICD release

Wasser,

Werthmann,

Hall

et al. 2023

Mol Neurodegeneration

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Background ApoE4, the most significant genetic risk factor for late-onset Alzheimer’s disease (AD), sequesters a pro-synaptogenic Reelin receptor, Apoer2, in the endosomal compartment and prevents its normal recycling. In the adult brain, Reelin potentiates excitatory synapses and thereby protects against amyloid-β toxicity. Recently, a gain-of-function mutation in Reelin that is protective against early-onset AD has been described. Alternative splicing of the Apoer2 intracellular domain (Apoer2-ICD) regulates Apoer2 signaling. Splicing of juxtamembraneous exon 16 alters the γ-secretase mediated release of the Apoer2-ICD as well as synapse number and LTP, and inclusion of exon 19 ameliorates behavioral deficits in an AD mouse model. The Apoer2-ICD has also been shown to alter transcription of synaptic genes. However, the role of Apoer2-ICD release upon transcriptional regulation and its role in AD pathogenesis is unknown. Methods To assess in vivo mRNA-primed ribosomes specifically in hippocampi transduced with Apoer2-ICD splice variants, we crossed wild-type, cKO, and Apoer2 cleavage-resistant mice to a Cre-inducible translating ribosome affinity purification (TRAP) model. This allowed us to perform RNA-Seq on ribosome-loaded mRNA harvested specifically from hippocampal cells transduced with Apoer2-ICDs. Results Across all conditions, we observed ~4,700 altered translating transcripts, several of which comprise key synaptic components such as extracellular matrix and focal adhesions with concomitant perturbation of critical signaling cascades, energy metabolism, translation, and apoptosis. We further demonstrated the ability of the Apoer2-ICD to rescue many of these altered transcripts, underscoring the importance of Apoer2 splicing in synaptic homeostasis. A variety of these altered genes have been implicated in AD, demonstrating how dysregulated Apoer2 splicing may contribute to neurodegeneration. Conclusions Our findings demonstrate how alternative splicing of the APOE and Reelin receptor Apoer2 and release of the Apoer2-ICD regulates numerous translating transcripts in mouse hippocampi in vivo. These transcripts comprise a wide range of functions, and alterations in these transcripts suggest a mechanistic basis for the synaptic deficits seen in Apoer2 mutant mice and AD patients. Our findings, together with the recently reported AD-protective effects of a Reelin gain-of-function mutation in the presence of an early-onset AD mutation in Presenilin-1, implicate the Reelin/Apoer2 pathway as a target for AD therapeutics. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Regulation of the hippocampal translatome by Apoer2-ICD release

Wasser,

Werthmann,

Hall

et al. 2023

Mol Neurodegeneration

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“…When crossed with the APP/PS1 line, Lrp6 mice demonstrated enhanced Aβ production leading to inhibition of Wnt signaling, a finding also seen in Alzheimer brains ( Liu et al, 2014 ). Interestingly, clozapine reduced β-catenin and TCF-4 (encoded by TCF7L2), an effect mediated through down-regulation of TNIK (Traf2- and Nck-interacting kinase) ( Yuan et al, 2021 ). TNIK is up-regulated by either Apoer2-ICD ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…4). The Wnt-signaling pathway, much like Reelin signaling, regulates brain development, synapse formation and synapse function (Inestrosa et al, 2012) ), an effect mediated through down-regulation of TNIK (Traf2-and Nck-interacting kinase) (Yuan et al, 2021). TNIK is up-regulated by either Apoer2-ICD (Fig.…”

Section: Disease Implicationsmentioning

confidence: 99%

Apoer2-ICD-dependent regulation of hippocampal ribosome mRNA loading

Wasser

Werthmann

Hall

et al. 2023

Preprint

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Background ApoE4, the most significant genetic risk factor for late-onset Alzheimer’s disease (AD), sequesters a pro-synaptogenic Reelin receptor, Apoer2, in the endosomal compartment and prevents its normal recycling. In the adult brain, Reelin potentiates excitatory synapses and thereby protects against amyloid-β toxicity. Recently, a gain-of-function mutation in Reelin that is protective against early-onset AD has been described. Alternative splicing of the Apoer2 intracellular domain (Apoer2-ICD) regulates Apoer2 signaling. Splicing of juxtamembraneous exon 16 alters the g-secretase mediated release of the Apoer2-ICD as well as synapse number and LTP, and inclusion of exon 19 ameliorates behavioral deficits in an AD mouse model. The Apoer2-ICD has also been shown to alter transcription of synaptic genes. However, the role of Apoer2 splicing for transcriptional regulation and its role in AD pathogenesis is unknown.Methods To assess in vivo mRNA-primed ribosomes specifically in hippocampi transduced with Apoer2-ICD splice variants, we crossed wild-type, cKO, and Apoer2 cleavage-resistant mice to a Cre-inducible translating ribosome affinity purification (TRAP) model. This allowed us to perform RNA-Seq on ribosome-loaded mRNA harvested specifically from hippocampal cells transduced with Apoer2-ICDs.Results Across all conditions, we observed ~ 4,700 altered ribosome-associated transcripts, several of which comprise key synaptic components such as extracellular matrix and focal adhesions with concomitant perturbation of critical signaling cascades, energy metabolism, translation, and apoptosis. We further demonstrated the ability of the Apoer2-ICD to rescue many of these altered transcripts, underscoring the importance of Apoer2 splicing in synaptic homeostasis. A variety of these altered genes have been implicated in AD, demonstrating how dysregulated Apoer2 splicing may contribute to neurodegeneration.Conclusions Our findings demonstrate how alternative splicing of the APOE and Reelin receptor Apoer2 and release of the Apoer2-ICD regulates numerous ribosome-associated transcripts in mouse hippocampi in vivo. These transcripts comprise a wide range of functions, and alterations in these transcripts suggest a mechanistic basis for the synaptic deficits seen in Apoer2 mutant mice and AD patients. Our findings, together with the recently reported AD-protective effects of a Reelin gain-of-function mutation in the presence of an early-onset AD mutation in Presenilin-1, implicate the Reelin/Apoer2 pathway as a target for AD therapeutics.

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