Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold

Grabrucker, Andreas M.; Schmeißer, Michael J.; Udvardi, Patrick T; Arons, Magali H; Schoen, Michael; Woodling, Nathaniel S.; Andreasson, Katrin I.; Hof, Patrick R.; Buxbaum, Joseph D.; Garner, Craig C.; Boeckers, Tobias M.

doi:10.1186/1750-1326-6-65

Cited by 71 publications

(57 citation statements)

References 61 publications

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“…Western Blots were performed as previously described (Grabrucker et al, 2011). Protein concentration was determined by Bradford Assay; equal amounts of protein were separated using SDS-PAGE (polyacrylamide gel electrophoresis) and subsequently blotted on nitrocellulose membrane (GE Healthcare, Germany).…”

Section: Methodsmentioning

confidence: 99%

FUS Mislocalization and Vulnerability to DNA Damage in ALS Patients Derived hiPSCs and Aging Motoneurons

Higelin

Demestre

Putz

et al. 2016

Front. Cell. Neurosci.

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Mutations within the FUS gene (Fused in Sarcoma) are known to cause Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease affecting upper and lower motoneurons. The FUS gene codes for a multifunctional RNA/DNA-binding protein that is primarily localized in the nucleus and is involved in cellular processes such as splicing, translation, mRNA transport and DNA damage response. In this study, we analyzed pathophysiological alterations associated with ALS related FUS mutations (mFUS) in human induced pluripotent stem cells (hiPSCs) and hiPSC derived motoneurons. To that end, we compared cells carrying a mild or severe mFUS in physiological- and/or stress conditions as well as after induced DNA damage. Following hyperosmolar stress or irradiation, mFUS hiPS cells recruited significantly more cytoplasmatic FUS into stress granules accompanied by impaired DNA-damage repair. In motoneurons wild-type FUS was localized in the nucleus but also deposited as small punctae within neurites. In motoneurons expressing mFUS the protein was additionally detected in the cytoplasm and a significantly increased number of large, densely packed FUS positive stress granules were seen along neurites. The amount of FUS mislocalization correlated positively with both the onset of the human disease (the earlier the onset the higher the FUS mislocalization) and the maturation status of the motoneurons. Moreover, even in non-stressed post-mitotic mFUS motoneurons clear signs of DNA-damage could be detected. In summary, we found that the susceptibility to cell stress was higher in mFUS hiPSCs and hiPSC derived motoneurons than in controls and the degree of FUS mislocalization correlated well with the clinical severity of the underlying ALS related mFUS. The accumulation of DNA damage and the cellular response to DNA damage stressors was more pronounced in post-mitotic mFUS motoneurons than in dividing hiPSCs suggesting that mFUS motoneurons accumulate foci of DNA damage, which in turn might be directly linked to neurodegeneration.

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Section: Methodsmentioning

confidence: 99%

FUS Mislocalization and Vulnerability to DNA Damage in ALS Patients Derived hiPSCs and Aging Motoneurons

Higelin

Demestre

Putz

et al. 2016

Front. Cell. Neurosci.

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“…One highly replicated ASD-risk gene is SHANK3 (SH3 and multiple ankyrin repeat domains 3), which is a synaptic scaffolding protein that https://doi.org/10.1016/j.ijdevneu.2018.10.003 Received 10 August 2018; Received in revised form 21 October 2018; Accepted 26 October 2018 plays a crucial role in synaptic plasticity (Naisbitt et al, 1999;Grabrucker et al, 2011). Heterozygous deletions or point mutations of SHANK3 are thought to be the main cause of Phelan-McDermid Syndrome (PMS, also referred to as 22q13 Deletion Syndrome)a genetic disorder characterized by global developmental delay, delayed or absent speech, moderate to severe intellectual disability, dysmorphic features, neonatal hypotonia, seizures, and a strong co-morbidity with ASD (Bonaglia et al, 2001(Bonaglia et al, , 2006Phelan, 2008;Phelan and McDermid, 2011;Harony-Nicolas et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Shank3B mutant mice display pitch discrimination enhancements and learning deficits

Rendall

Perrino

Buscarello

et al. 2018

Intl J of Devlp Neuroscience

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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a core set of atypical behaviors in social‐communicative and repetitive‐motor domains. Individual profiles are widely heterogeneous and include language skills ranging from nonverbal to hyperlexic. The causal mechanisms underlying ASD remain poorly understood but appear to include a complex combination of polygenic and environmental risk factors. SHANK3 (SH3 and multiple ankyrin repeat domains 3) is one of a subset of well‐replicated ASD‐risk genes (i.e., genes demonstrating ASD associations in multiple studies), with haploinsufficiency of SHANK3 following deletion or de novo mutation seen in about 1% of non‐syndromic ASD. SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. In order to more closely evaluate the contribution of SHANK3 to neurodevelopmental expression of ASD, a knockout mouse model with a mutation in the PDZ domain was developed. Initial research showed compulsive/repetitive behaviors and impaired social interactions in these mice, replicating two core ASD features. The current study was designed to further examine Shank3B heterozygous and homozygous knockout mice for behaviors that might map onto atypical language in ASD (e.g., auditory processing, and learning/memory). We report findings of repetitive and atypical aggressive social behaviors (replicating prior reports), novel evidence that Shank3B KO mice have atypical auditory processing (low‐level enhancements that might have a direct relationship with heightened pitch discrimination seen in ASD), as well as robust learning impairments.

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“…8 The application of soluble amyloid β-protein (Aβ) decreases the ProSAP2/ Shank3 levels in the PSD, and this change in turn leads to reductions in Shank1 protein and synapse density in hippocampal neurons, whereas the level of the Shank2 protein is increased. 9,10 In AD, the process of synaptic damage could involve a beginning with dysregulation of synapse-related proteins such as PSD95 and Shank1. 11 AD patients with MCI demonstrated loss of postsynaptic markers such as PSD95 and Shank1.…”

Section: Introductionmentioning

confidence: 99%

Effects of curcumin on synapses in APPswe/PS1dE9 mice

Wang

Wei

et al. 2016

Int J Immunopathol Pharmacol

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Significant losses of synapses have been demonstrated in studies of Alzheimer's disease (AD), but structural and functional changes in synapses that depend on alterations of the postsynaptic density (PSD) area occur prior to synaptic loss and play a crucial role in the pathology of AD. Evidence suggests that curcumin can ameliorate the learning and memory deficits of AD. To investigate the effects of curcumin on synapses, APPswe/PS1dE9 double transgenic mice (an AD model) were used, and the ultra-structures of synapses and synapse-associated proteins were observed. Six months after administration, few abnormal synapses were observed upon electron microscopy in the hippocampal CA1 areas of the APPswe/PS1dE9 double transgenic mice. The treatment of the mice with curcumin resulted in improvements in the quantity and structure of the synapses. Immunohistochemistry and western blot analyses revealed that the expressions of PSD95 and Shank1 were reduced in the hippocampal CA1 areas of the APPswe/PS1dE9 double transgenic mice, but curcumin treatment increased the expressions of these proteins. Our findings suggest that curcumin improved the structure and function of the synapses by regulating the synapse-related proteins PSD95 and Shank1.

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Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold

Cited by 71 publications

References 61 publications

FUS Mislocalization and Vulnerability to DNA Damage in ALS Patients Derived hiPSCs and Aging Motoneurons

FUS Mislocalization and Vulnerability to DNA Damage in ALS Patients Derived hiPSCs and Aging Motoneurons

Shank3B mutant mice display pitch discrimination enhancements and learning deficits

Effects of curcumin on synapses in APPswe/PS1dE9 mice

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