The cellular modifier MOAG‐4/SERF drives amyloid formation through charge complementation

Pras, Anita; Houben, Bert; Aprile, Francesco A.; Seinstra, Renée I.; Gallardo, Rodrigo; Janssen, Leen; Hogewerf, Wytse; Gallrein, Christian; Vleeschouwer, Matthias De; Mata‐Cabana, Alejandro; Koopman, Mandy; Stroo, Esther; Vries, Minke de; Edwards, Samantha Louise; Kirstein, Janine; Vendruscolo, Michele; Falsone, S. Fabio; Rousseau, Frédéric; Schymkowitz, Joost; Nollen, Ellen A. A.

doi:10.15252/embj.2020107568

Cited by 19 publications

(35 citation statements)

References 74 publications

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“…In this regard, it was recently seen in humans and C. elegans that there is a small, disordered and highly conserved protein called SERF (human)/MOAG-4 ( C. elegans ), which has a strong ability to accelerate the primary nucleation of aggregator-prone proteins such as Aβ or α-synuclein [ 37 ]. This process appears to be mediated by SERF/MOAG-4 interactions with negatively charged segments in aggregation-prone proteins [ 38 ]. These charge interactions between cellular modifiers and amyloidogenic proteins could be new therapeutic targets to block the generation of toxic oligomers.…”

Section: C Elegans Models To Study the Mechanism Of Toxicity...mentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase.

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Section: C Elegans Models To Study the Mechanism Of Toxicity...mentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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“…For MD simulations proteins were embedded in a box of water of 12 × 12 × 12 nm 57 and neutralized by sodium and chloride ions. All simulations were performed with the GROMACS 2018 version 19 and a timestep of 2 fs. Explicit water was represented by the TIP3P model 57 , 58 , while the protein and ions were defined by the CHARMM36m force field 59 .…”

Section: Methodsmentioning

confidence: 99%

“…The aggregation propensity of HTT is regulated by molecular chaperones, and the modulation of expression for Hsp70, J-domain proteins (JDPs), Hsp110, NAC, TRiC, and MOAG-4/SERF have been demonstrated to reduce HTT/polyQ aggregation and toxicity in various model systems [11][12][13][14][15][16][17][18][19] . Yet, a complete suppression of HTTExon1Q 48 aggregation could only be shown for the trimeric chaperone complex, composed of Hsc70, a class II J-domain protein (JDP), and the nucleotide exchange factor Apg2 18 .…”

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confidence: 99%

Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT

et al. 2022

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Huntington’s disease is a neurodegenerative disease caused by an expanded polyQ stretch within Huntingtin (HTT) that renders the protein aggregation-prone, ultimately resulting in the formation of amyloid fibrils. A trimeric chaperone complex composed of Hsc70, DNAJB1 and Apg2 can suppress and reverse the aggregation of HTTExon1Q48. DNAJB1 is the rate-limiting chaperone and we have here identified and characterized the binding interface between DNAJB1 and HTTExon1Q48. DNAJB1 exhibits a HTT binding motif (HBM) in the hinge region between C-terminal domains (CTD) I and II and binds to the polyQ-adjacent proline rich domain (PRD) of soluble as well as aggregated HTT. The PRD of HTT represents an additional binding site for chaperones. Mutation of the highly conserved H244 of the HBM of DNAJB1 completely abrogates the suppression and disaggregation of HTT fibrils by the trimeric chaperone complex. Notably, this mutation does not affect the binding and remodeling of any other protein substrate, suggesting that the HBM of DNAJB1 is a specific interaction site for HTT. Overexpression of wt DNAJB1, but not of DNAJB1H244A can prevent the accumulation of HTTExon1Q97 aggregates in HEK293 cells, thus validating the biological significance of the HBM within DNAJB1.

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“…This peptide was dubbed mo difier of ag gregation-4 (MOAG-4) and was found to be an ortholog of two human proteins: SERF1A and SERF2. Interestingly, SERF proteins accelerate the aggregation of multiple amyloidogenic proteins in vitro , but not non-amyloidogenic proteins 29–31 . This aggregation promoting effect has been accredited to the interaction of a highly positively charged N-terminal segment with segments of the aggregation-prone proteins that are enriched in negatively charged and hydrophobic, aromatic amino acids leading to the disruption of its inter- and intramolecular electrostatic interactions 31–34 .…”

Section: Introductionmentioning

confidence: 99%

“…This aggregation promoting effect has been accredited to the interaction of a highly positively charged N-terminal segment with segments of the aggregation-prone proteins that are enriched in negatively charged and hydrophobic, aromatic amino acids leading to the disruption of its inter-and intramolecular electrostatic interactions [31][32][33][34] . Neutralizing the charge of MOAG-4 and SERF2 in this N-terminal segment is sufficient to suppress their effect on aggregation and to reduce toxicity in C. elegans models for polyglutamine and Aβ pathology 34 . In this study, we use the established APPPS1-21 mouse model for Aβ-pathology to investigate whether the removal of SERF2 also modifies the aggregation of amyloidogenic proteins in the biologically more complex environment of the mammalian brain.…”

Section: Introductionmentioning

confidence: 99%

SERF deletion modifies amyloid aggregation in a mouse model of Alzheimer’s disease

Stroo

Janssen

Sin

et al. 2021

Preprint

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Neurodegenerative diseases like Alzheimer, Parkinson and Huntington disease are characterized by aggregation-prone proteins that form amyloid fibrils through a nucleation process. Despite the shared β-sheet structure, recent research has shown that structurally different polymorphs exist within fibrils of the same protein. These polymorphs are associated with varying levels of toxicity and different disease phenotypes. MOAG-4 and its human orthologs SERF1 and SERF2 have previously been shown to modify the nucleation and drive amyloid formation and protein toxicity in vitro and in C. elegans. To further explore these findings, we generated a Serf2 knockout (KO) mouse model and crossed it with the APPPS1 mouse model for Aβ amyloid pathology. Full-body KO of Serf2 resulted in a developmental delay and perinatal lethality due to insufficient lung maturation. Therefore, we proceeded with a brain-specific Serf2 KO, which was found to be viable. We examined the Aβ pathology at 1 and 3 months of age, which is before and after the start of amyloid deposition. We show that SERF2 deficiency does not affect the production and overall Aβ levels. Serf2 KO-APPPS1 mice displayed an increased intracellular Aβ accumulation at 1 month and a higher number of Aβ deposits compared to APPPS1 mice with similar Aβ levels. Moreover, conformation-specific dyes and electron microscopy revealed a difference in the structure and amyloid content of these Aβ deposits. Together, our results reveal that SERF2 causes a structural shift in Aβ aggregation in a mammalian brain. These findings indicate that a single endogenous factor may contribute to amyloid polymorphisms, allowing for new insights into this phenomenon’s contribution to disease manifestation.HighlightsLoss of SERF2 slows embryonic development and causes perinatal lethalitySERF2 affects proliferation in a cell-autonomous fashionBrain-specific Serf2 knockout does not affect viability or Aβ productionBrain deletion of Serf2 shifts the amyloid conformation of Aβ

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The cellular modifier MOAG‐4/SERF drives amyloid formation through charge complementation

Cited by 19 publications

References 74 publications

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT

SERF deletion modifies amyloid aggregation in a mouse model of Alzheimer’s disease

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