15 Works

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Rebecca Sims, Sven J Van Der Lee, Adam C Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W Kunkle, Anne Boland, Rachel Raybould, Joshua C Bis, Eden R Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R Graham, Robert Olaso, Per Hoffmann, Megan L Grove, Badri N Vardarajan, Mikko Hiltunen, Markus M Nöthen … & Gerard D Schellenberg
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed...

Analysis of shared heritability in common disorders of the brain.

Brainstorm Consortium, Verneri Anttila, Brendan Bulik-Sullivan, Hilary K Finucane, Raymond K Walters, Jose Bras, Laramie Duncan, Valentina Escott-Price, Guido J Falcone, Padhraig Gormley, Rainer Malik, Nikolaos A Patsopoulos, Stephan Ripke, Zhi Wei, Dongmei Yu, Phil H Lee, Patrick Turley, Benjamin Grenier-Boley, Vincent Chouraki, Yoichiro Kamatani, Claudine Berr, Luc Letenneur, Didier Hannequin, Philippe Amouyel, Anne Boland … & Robin Murray
Disorders of the brain can exhibit considerable epidemiological comorbidity and share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 215,683 patients and 657,164 controls, and their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, while neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identify significant sharing between disorders and a...

TET2 Regulates the Neuroinflammatory Response in Microglia.

Alejandro Carrillo-Jimenez, Özgen Deniz, Maria Victoria Niklison-Chirou, Rocio Ruiz, Karina Bezerra-Salomão, Vassilis Stratoulias, Rachel Amouroux, Ping Kei Yip, Anna Vilalta, Mathilde Cheray, Alexander Michael Scott-Egerton, Eloy Rivas, Khadija Tayara, Irene García-Domínguez, Juan Garcia-Revilla, Juan Carlos Fernandez-Martin, Ana Maria Espinosa-Oliva, Xianli Shen, Peter St George-Hyslop, Guy Brown, Petra Hajkova, Bertrand Joseph, Jose Luis Venero, Miguel Ramos Branco & Miguel Angel Burguillos

Longitudinal evaluation of Tau-P301L transgenic mice reveals no cognitive impairments at 17 months of age.

Brianne A Kent, Christopher J Heath, Chi Hun Kim, Rosemary Ahrens, Paul E Fraser, Peter St George-Hyslop, Timothy Bussey & Lisa Saksida
Tau is a microtubule-associated binding protein implicated in neurodegenerative tauopathies, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD). These diseases result in the intracellular accumulation of hyperphosphorylated tau in the form of neurofibrillary tangles, the presence of which is associated with cognitive deficits. We conducted a longitudinal behavioral study to provide a profile of the TgTau(P301L)23027 transgenic mouse in multiple cognitive domains across multiple ages. P301L is the tau mutation most frequently observed in patients...

RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

Ya-Cheng Liao, Michael Fernandopulle, Guozhen Wang, Heejun Choi, Ling Hao, Catherine M Drerup, Seema Qamar, Jonathon Nixon-Abell, Yi Shen, William Meadows, Michele Vendruscolo, Tuomas Knowles, Matthew Nelson, Magda Czekalska, Greta Musteikyte, Rajan Patel, Christina Stephens, Amalia Pasolli, Lucy Forrest, Peter St George-Hyslop, Jennifer Lippincott-Schwartz & Michael E Ward
Long-distance RNA transport enables local protein synthesis at metabolicallyactive sites distant from the nucleus. This process ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a mechanism for RNA transport in which RNA granules “hitchhike” on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proximity labeling proteomics reveal that annexin A11 (ANXA11), an RNA granule-associated phosphoinositide-binding protein, acts as a molecular tether between RNA granules...

Calcium binding at the C-terminus of α-synuclein modulates synaptic vesicle interaction

Gabriele Kaminski, Janin Lautenschlager, Amberley Barrett, Giuliana Fusco, Florian Stroehl, Nathan Curry, Maria Zacharopoulou, Claire Michel, Romain Laine, Nadezda Nespovitaya, Marcus Fantham, Dorothea Pinotsi, Wagner Zago, Paul Fraser, Anurag Tandon, Peter St George-Hyslop, Eric Rees, Jonathan Phillips, Alfonso De Simone & Clemens Kaminski
Alpha-synuclein is known to bind to small unilamellar vesicles (SUVs) via its N-terminus which forms an amphipathic alpha-helix upon membrane interaction. Here we show that calcium binds to the C-terminus of alpha-synuclein, therewith increasing its lipid binding capacity. Using CEST-NMR we reveal that alpha-synuclein interacts with isolated synaptic vesicles with two regions, the N-terminus, already known from studies on SUVs, and additionally via its C-terminus, which is regulated by the binding of calcium. Indeed, dSTORM...

FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions.

Seema Qamar, Guozhen Wang, Suzanne J Randle, Francesco Ruggeri, Juan Varela, Qiaojin Lin, Emma C Phillips, Akinori Miyashita, Declan Williams, Florian Ströhl, William Meadows, Rodylyn Ferry, Victoria J Dardov, Gian G Tartaglia, Lindsay A Farrer, Gabriele Kaminski, Clemens Kaminski, Christine Holt, Paul E Fraser, Gerold Schmitt-Ulms, David Klenerman, Tuomas Knowles, Michele Vendruscolo & Peter St George-Hyslop

The physiological and pathological biophysics of phase separation and gelation of RNA binding proteins in amyotrophic lateral sclerosis and fronto-temporal lobar degeneration.

Peter St George-Hyslop, Qiaojin Lin, Akinori Miyashita, Emma C Phillips, Seema Qamar, Suzanne J Randle & GuoZhen Wang
Many RNA binding proteins, including FUS, contain moderately repetitive, low complexity, intrinsically disordered domains. These sequence motifs have recently been found to underpin reversible liquid: liquid phase separation and gelation of these proteins, permitting them to reversibly transition from a monodispersed state to liquid droplet- or hydrogel-like states. This function allows the proteins to serve as scaffolds for the formation of reversible membraneless intracellular organelles such as nucleoli, stress granules and neuronal transport granules. Using...

Phase Separation of FUS is Modulated by Methylation State of Cation-π Interactions and Interaction with TNPO1

Peter St George-Hyslop, Seema Qamar, Guozhen Wang, SJ Randle, Francesco Simone Ruggeri, Juan Varela, Clemens Kaminski, Gabriele Kaminski, Michele Vendruscolo, Tuomas Knowles, David Klenerman, Christine Holt, Qiaojin Lin & William Meadows
Reversible phase separation, which underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles, is in part driven by the intrinsically disordered low complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which...

Inherited and Sporadic Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degenerations arising from Pathological Condensates of Phase Separating Proteins.

Michael Fernandopulle, GuoZhen Wang, Jonathon Nixon-Abell, Seema Qamar, Varun Balaji, Ryuta Morihara & Peter St George-Hyslop
Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal...

A novel Alzheimer disease locus located near the gene encoding tau protein.

G Jun, CA Ibrahim-Verbaas, M Vronskaya, J-C Lambert, J Chung, AC Naj, BW Kunkle, L-S Wang, JC Bis, C Bellenguez, D Harold, KL Lunetta, AL Destefano, B Grenier-Boley, R Sims, GW Beecham, AV Smith, V Chouraki, KL Hamilton-Nelson, MA Ikram, N Fievet, N Denning, ER Martin, H Schmidt, Y Kamatani … & LA Farrer

C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction.

Janin Lautenschläger, Amberley D Stephens, Giuliana Fusco, Florian Ströhl, Nathan Curry, Maria Zacharopoulou, Claire Michel, Romain Laine, Nadezhda Nespovitaya, Marcus Fantham, Dorothea Pinotsi, Wagner Zago, Paul Fraser, Anurag Tandon, Peter St George-Hyslop, Eric Rees, Jonathan J Phillips, Alfonso De Simone, Clemens Kaminski & Gabriele S Kaminski Schierle

Ultra-rare mutations in SRCAP segregate in Caribbean Hispanic families with Alzheimer disease.

Badri N Vardarajan, Giuseppe Tosto, Roger Lefort, Lei Yu, David A Bennett, Philip L De Jager, Sandra Barral, Dolly Reyes-Dumeyer, Peter L Nagy, Joseph H Lee, Rong Cheng, Martin Medrano, Rafael Lantigua, Ekaterina Rogaeva, Peter St George-Hyslop & Richard Mayeux

TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant

P Thornton, J Sevalle, Michael Deery, G Fraser, Y Zhou, S Ståhl, EH Franssen, Roger Dodd, Seema Qamar, B Gomez Perez-Nievas, LSC Nicol, S Eketjäll, J Revell, C Jones, A Billington, Peter St George-Hyslop, I Chessell & D Crowther
We have characterised the proteolytic cleavage events responsible for the shedding of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine microglia and TREM2-expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N-terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases...

SORL1 mutations in early- and late-onset Alzheimer disease.

Michael L Cuccaro, Regina M Carney, Yalun Zhang, Christopher Bohm, Brian W Kunkle, Badri N Vardarajan, Patrice L Whitehead, Holly N Cukier, Richard Mayeux, Peter St George-Hyslop & Margaret A Pericak-Vance

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