Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease

Lee, Linda; Dale, Elena; Staniszewski, Agnes; Zhang, Hong; Saeed, Faisal; Sakurai, Mikako; Fà, Mauro; Orozco, Ian J.; Michelassi, Francesco; Akpan, Nsikan; Lehrer, Helaina; Arancio, Ottavio

doi:10.1038/srep07190

Cited by 80 publications

(89 citation statements)

References 81 publications

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“…Measuring USVs is widely carried out in genetic ASD model mice (63), with phenotypes observed in models of Foxp1 (64), Cntnap2 (52), Tsc1 (20), Tsc2 (65), Nlgn3 (66), Nlgn4 (67), Shank1 (68), Shank2 (69), Shank3 (70) and Mecp2 (71). In support of our behavioral results, two recent studies have demonstrated that sumoylation in hippocampus can modify mammalian cognitive behaviors by altering hippocampal-dependent learning and memory by Ubc9, a E2 conjugating enzyme (72), and spatial memory by sumoylation of CREB (73). In addition, neuron-specific knockdown of all SUMO-1/2/3 in RNAi transgenic mice leads to anxiety-like behavior, and impairs episodic and fear memories (74).…”

Section: Discussionsupporting

confidence: 88%

Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

Usui

Harper

et al. 2017

Biological Psychiatry

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Background Mutations in the gene encoding the transcription factor forkhead box P2, FOXP2, result in brain developmental abnormalities including reduced gray matter in both human patients and rodent models, and speech and language deficits. However, neither the region-specific function of FOXP2 in the brain, in particular the cerebellum, nor the effects of any post-translational modifications of FOXP2 in the brain and disorders have been explored. Methods We characterized sumoylation of FOXP2 biochemically, and analyzed the region-specific function and sumoylation of FOXP2 in the developing mouse cerebellum. Using in utero electroporation to manipulate the sumoylation-state of Foxp2 as well as Foxp2 expression levels in Purkinje cells (PCs) of the cerebellum in vivo, we reduced Foxp2 expression approximately 40% in the mouse cerebellum. Such a reduction approximates the haploinsufficiency observed in human patients who demonstrate speech and language impairments. Results We identified sumoylation of FOXP2 at K674 (K673 in mouse) in the cerebellum of neonates. In vitro co-immunoprecipitation and in vivo colocalization experiments suggest that PIAS3 acts as the SUMO E3 ligase for FOXP2 sumoylation. This sumoylation modifies transcriptional regulation by FOXP2. We demonstrate that Foxp2 sumoylation is required for regulation of cerebellar motor function and vocal communication, likely through dendritic outgrowth and arborization of PCs in the mouse cerebellum. Conclusions Sumoylation of Foxp2 in neonatal mouse cerebellum regulates PC development as well as motor functions and vocal communication, demonstrating evidence for sumoylation in regulating mammalian behaviors.

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Section: Discussionsupporting

confidence: 88%

Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

Usui

Harper

et al. 2017

Biological Psychiatry

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“…Based on various AD mouse models, several studies indicated changes in global levels of SUMO1 conjugates during amyloid pathology (Lee et al., 2014; Marcelli et al., 2017; McMillan, Brown, Henley & Cimarosti, 2011; Nistico et al., 2014). Accordingly, we tested whether these findings can be recapitulated in our His 6 ‐HA‐SUMO1::5XFAD model by making use of the HA tag for high‐affinity detection of SUMO1 conjugates.…”

Section: Resultsmentioning

confidence: 99%

“…Variation in global SUMO1 levels in the context of increased amyloid burden was reported in different AD mouse models (Lee et al., 2014; McMillan et al., 2011; Nistico et al., 2014). For instance, in young (3–6 months old) Tg2576 animals, SUMO1 conjugate levels in hippocampal and cortical tissues were found to be increased, while SUMO1 levels at later stage (17 months old) were comparable to those of age‐matched control animals (Marcelli et al., 2017; McMillan et al., 2011; Nistico et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, several AD‐related proteins (such as α‐synuclein, tau, and APP) have been proposed to be SUMO1 conjugates (Martins et al., 2016). Additionally, SUMOylation levels have been correlated to synaptic plasticity and cognitive function in normal physiology and amyloid beta pathology (Lee et al., 2014; Marcelli et al., 2017). Therefore, understanding the role of SUMOylation is particularly interesting not only during age‐related neurodegenerative stress such as AD but also during physiological aging (Andreou & Tavernarakis, 2009; Feligioni et al., 2015; Krumova & Weishaupt, 2013; Liebelt & Vertegaal, 2016).…”

Section: Introductionmentioning

confidence: 99%

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SUMO1‐conjugation is altered during normal aging but not by increased amyloid burden

et al. 2018

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SummaryA proper equilibrium of post‐translational protein modifications is essential for normal cell physiology, and alteration in these processes is key in neurodegenerative disorders such as Alzheimer's disease. Recently, for instance, alteration in protein SUMOylation has been linked to amyloid pathology. In this work, we aimed to elucidate the role of protein SUMOylation during aging and increased amyloid burden in vivo using a His6‐HA‐SUMO1 knock‐in mouse in the 5XFAD model of Alzheimer's disease. Interestingly, we did not observe any alteration in the levels of SUMO1‐conjugation related to Alzheimer's disease. SUMO1 conjugates remained localized to neuronal nuclei upon increased amyloid burden and during aging and were not detected in amyloid plaques. Surprisingly however, we observed age‐related alterations in global levels of SUMO1 conjugation and at the level of individual substrates using quantitative proteomic analysis. The identified SUMO1 candidate substrates are dominantly nuclear proteins, mainly involved in RNA processing. Our findings open novel directions of research for studying a functional link between SUMOylation and its role in guarding nuclear functions during aging.

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“…Nicastrin is required for the assembly of presenilin complexes to mediate Notch signalling and for processing and trafficking of β-amyloid precursor protein and thus plays a role in amyloid plaque formation [46]. Proper signalling between presenilin and nicastrin is important not only for processing of APP and accumulation of Aβ peptides but also for synaptic plasticity [47]. The next component of γ-secretase complex is PEN-2, a membrane protein with two predicted transmembrane domains, both N′ and C′ terminals are in extracellular space and with hydrophilic cytosolic loop [48].…”

Section: The γ-Secretase Complex Partnersmentioning

confidence: 99%

Presenilins Interactome in Alzheimer’s Disease and Pathological Ageing

Wężyk¹,

Żekanowski²

2017

Senescence - Physiology or Pathology

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Alzheimer's disease (AD) is the most common type of dementia characterized by massive neuronal loss. Pathological hallmarks of the disease are overproduction of β-amyloid (Aβ) and hyperphosphorylation of tau protein accumulated into senile plaques (SPs) and neurofibrillary tangles (NFTs), respectively. SPs with cortical tau pathology are also hallmark of pathological ageing (PA). Recently, an extensive overlap has been shown between Aβ levels and profiles in PA and AD brains, suggesting that PA could be a prodromal AD phase. Presenilins are major components of the γ-secretase complex involved in Aβ production. Furthermore, presenilins interact with players of numerous signalling pathways important in the PA and AD. Integration of various modern research approaches would reinforce the role of presenilins signalling network in brain pathology. These approaches include high-throughput (epi)genetic and transcriptomic analyses, large-scale microscopic imaging studies, immunoaffinity purification or mass spectrometry. Comprehensive integration of these methods is necessary to update the definition of the role of presenilins in AD and PA. Hereby, we summarize the available data on presenilins' functions and interactions. We believe that the systematization of the existing knowledge will stimulate further research and will help reveal the molecular nooks and crannies in Alzheimer's disease and in pathological ageing.

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Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease

Cited by 80 publications

References 81 publications

Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

SUMO1‐conjugation is altered during normal aging but not by increased amyloid burden

Presenilins Interactome in Alzheimer’s Disease and Pathological Ageing

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