Gai Ayalon

A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

Common variant genome-wide association studies (GWASs) have, to date, identified >24 risk loci for Parkinsons disease (PD). To discover additional loci, we carried out a GWAS comparing 6,476 PD cases with 302,042 controls, followed by a meta-analysis with a recent study of over 13,000 PD cases and 95,000 controls at 9,830 overlapping variants. We then tested 35 loci (P < 1 × 10−6) in a replication cohort of 5,851 cases and 5,866 controls. We identified 17 novel risk loci (P < 5 × 10−8) in a joint analysis of 26,035 cases and 403,190 controls. We used a neurocentric strategy to assign candidate risk genes to the loci. We identified protein-altering or cis–expression quantitative trait locus (cis-eQTL) variants in linkage disequilibrium with the index variant in 29 of the 41 PD loci. These results indicate a key role for autophagy and lysosomal biology in PD risk, and suggest potential new drug targets for PD.

Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration

Loss of dual leucine zipper kinase results in attenuated JNK/c-Jun stress response pathway activation and reduced neuronal degeneration after kainic acid–induced excitotoxic seizures.

EVALUATION OF TAU BURDEN IN A CROSS-SECTIONAL COHORT OF ALZHEIMER’S DISEASE SUBJECTS USING [18F]GTP1 (GENENTECH TAU PROBE 1)

P4-351 EVALUATION OF TAU BURDEN IN A CROSSSECTIONALCOHORTOFALZHEIMER’SDISEASE SUBJECTS USING [F]GTP1 (GENENTECH TAU PROBE 1) Sandra Sanabria Bohorquez, Olivier Barret, Gilles Tamagnan, David Alagille, Jan Marik, Gai Ayalon, Thomas Bengtsson, Alex de Crespigny, Danna Jennings, John P. Seibyl, Kenneth Marek, Robby Weimer, Geoffrey A. Kerchner, Genentech, Inc., South San Francicso, CA, USA; Molecular Neuroimaging, LLC, New Haven, CT, USA; 3 Genentech, Inc., South San Francisco, CA, USA. Contact e-mail: sanabris@gene.com

High-throughput screening of antibody variants for chemical stability: identification of deamidation-resistant mutants

ABSTRACT Developability assessment of therapeutic antibody candidates assists drug discovery by enabling early identification of undesirable instabilities. Rapid chemical stability screening of antibody variants can accelerate the identification of potential solutions. We describe here the development of a high-throughput assay to characterize asparagine deamidation. We applied the assay to identify a mutation that unexpectedly stabilizes a critical asparagine. Ninety antibody variants were incubated under thermal stress in order to induce deamidation and screened for both affinity and total binding capacity. Surprisingly, a mutation five residues downstream from the unstable asparagine greatly reduced deamidation. Detailed assessment by LC-MS analysis confirmed the predicted improvement. This work describes both a high-throughput method for antibody stability screening during the early stages of antibody discovery and highlights the value of broad searches of antibody sequence space.

A PHASE I STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF RO7105705 IN HEALTHY VOLUNTEERS AND PATIENTS WITH MILD-TO-MODERATE AD

O2-17-03 A PHASE I STUDY TO EVALUATE THE SAFETYAND TOLERABILITY OF RO7105705 IN HEALTHY VOLUNTEERS AND PATIENTS WITH MILD-TOMODERATE AD Geoffrey A. Kerchner, Gai Ayalon, Flavia Brunstein, Priya Chandra, Akash Datwani, Reina N. Fuji, Paul T. Manser, Anjali Vaze, Michael Ward, Kristin R. Wildsmith, Corinne Foo-Atkins, Genentech, South San Francisco, CA, USA; Genentech, Inc., South San Francisco, CA, USA. Contact e-mail: kerchner.geoffrey@gene.com

Identification and Characterization of Reconstituted α-Synuclein, Amyloid-β and Tau Fibrils by Immunogold Negative Staining Electron Microscopy

Neurodegenerative diseases are a major public health concern in the aging population worldwide. Clinically, neurodegeneration manifests as cognitive decline and pathologically by dysfunction and loss of synapses, aggregation of misfolded proteins and progressive neuronal cell loss. The two most common neurodegenerative diseases are Alzheimer’s disease, characterized by accumulation of betaamyloid plaques and neurofibrillary tau tangles, and Parkinson’s disease, characterized by Lewy Bodies comprised of the protein alpha synuclein. In Alzheimer’s disease and Parkinson’s disease, the anatomical distribution and burden of tau tangles and synuclein Lewy bodies, respectively, correlate with progression of disease symptoms. These higher order structures of aggregated proteins are believed to originate with misfolded protein monomers that assemble into low molecular weight oligomers, which eventually form protein fibrils [1].

Tau antibodies lacking effector function minimize inflammatory responses while effectively blocking spread of tau pathology

P2-054 TAU ANTIBODIES LACKING EFFECTOR FUNCTION MINIMIZE INFLAMMATORY RESPONSES WHILE EFFECTIVELY BLOCKING SPREAD OF TAU PATHOLOGY Seung-Hye Lee, Claire Le Pichon, Oskar Adolfsson, Val erie Gafner, Maria Pihlgren, Han Lin, Hilda Solanoy, Robert Brendza, Hai Ngu, Oded Foreman, Ruby Chan, James Ernst, Danielle Dicara, Isidro Hotzel, Karpagam Srinivasan, David Hansen, Jasvinder Atwal, Andrea Pfeifer, Ryan Watts, Andreas Muhs, Kimberly Scearce-Levie, Gai Ayalon, Genentech, Inc., South San Francisco, CA, USA; National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA; AC Immune SA, Lausanne, Switzerland. Contact e-mail: lee.seunghye@gene.com