Tau and Beyond: Phosphorylation in Neurodegenerative Disorders

This meeting is being held jointly with the American Chemical Society's New York Section.

Organizers: Steven Braithwaite, Wyeth Research and Marco Baptista, Schering-Plough

Speakers: Peter Davies, Albert Einstein College of Medicine; Paul Lombroso, Yale University; Steven P. Braithwaite, Wyeth Research; Hilal Lashuel, Swiss Federal Institute of Technology Lausanne; William Dauer, Columbia University

Phosphorylation is a key regulatory mechanism controlling normal cellular function. In the field of neurodegeneration the hyperphosphorylation of tau has been the focus of the majority of research and drug development over the past decade. However, recent studies have proven this is only the tip of the iceberg, with phosphorylation being a critical process that can underlie the pathophysiological state in Alzheimer's Disease, Parkinsonism and stroke.

In this symposium we will address where research on tau has taken us and how a number of other kinases, phosphatases and phosphorylation events can increase our understanding of these disorders, leading to the development of novel therapeutic strategies.

The BPDG at the New York Academy of Sciences represents a diverse group of scientists and others with an interest in biochemistry, molecular biology, biomedical research, and related areas. Members are from pharmaceutical and biotechnology companies, and university and medical center research facilities across the Eastern United States. The group also serves as the Biochemical Topical Group for the American Chemical Society's New York Section. The purpose of the BPDG is to bring together diverse institutions and communities, industrial and academic, to share new and relevant information at the frontiers of research and development.

Presentations

STEP and Alzheimer's Disease
Paul Lombroso, Yale University

Dr. Lombroso research interests center around the characterization of a brain-specific tyrosine phosphatase termed STriatal-Enriched protein tyrosine Phosphatase (STEP). STEP is involved in regulating the activity of several key signaling proteins and receptors in the postsynaptic terminal. The current model of STEP function is that it opposes the development of synaptic strengthening. Substrates of STEP identified to date include ERK1/2, p38, Fyn and subunits of both the NMDAR and AMPAR receptors. In the case of ERK1/2, p38, and Fyn, STEP dephosphorylates a regulatory tyrosine in their activation loop and inactivates them. Relevant to today's talk, STEP dephosphorylates tyrosine (tyr¹⁴⁷²) on the NR2B subunit of the NMDAR, which promotes the internalization of NMDAR (NR1/NR2B) complexes. Recent evidence has shown that STEP also regulates GluR1/GluR2 receptor internalization, although the site that STEP dephosphorylates on GluR2 is not yet identified. Dr. Lombroso will present recent findings that STEP is normally a target for the ubiquitin proteasome system (UPS). STEP levels are significantly increased in mouse models of Alzheimer's disease (AD) and in human AD cortical tissue as a result of beta amyloid disruption of the UPS. Increased STEP levels are responsible for greater internalization of both AMPARs and NMDARs. Data will be presented from STEP KO mice that support this hypothesis. This is a novel mechanism that contributes to the pathophysiology of Alzheimer's disease by specifically disrupting normal synaptic function.

JNKs in Alzheimer's Disease, Parkinsonism and Stroke
Steven P. Braithwaite, Wyeth Research

The JNK pathway is activated in models of Parkinson's Disease, Alzheimer's Disease and stroke. The pathway is activated by multiple triggers, including cellular stress, and has a multitude of effects, primarily in leading to apoptosis. Therefore, it is potentially central in neurodegenerative disorders linking pathogenic inputs to neuronal death. We have studied the roles of JNK family members in a number of neurodegenerative disorders and sought to investigate the mechanisms by which they may contribute to pathology. Our studies lead to insights into the potential role of the JNK pathway on phosphorylation of nuclear and extranuclear targets, including tau. Our findings add to the importance of the JNK pathway in neurodegenerative disorders and investigate its potential as a therapeutic target.

α-Synuclein Phosphorylation in Parkinson's Disease and Related Synucleinopathies
Hilal Lashuel, Swiss Federal Institute of Technology Lausanne

Increasing evidence suggests that phosphorylation plays an important role in the oligomerization, fibrillization, Lewy body (LB) formation, and neurotoxicity of α-synuclein in Parkinson's disease (PD) and related synucleinopathies. However, whether phosphorylation promotes or inhibits α-syn aggregation and neurotoxicity in vivo remains unknown. This understanding is critical for elucidating the role of α-syn in the pathogenesis of PD and for development of therapeutic strategies for PD. In my talk, I will present recent studies from our laboratory aimed at i) elucidating the role of phosphorylation on modulating the structure, aggregation, membrane binding, subcellular localization and neurotoxicity of monomeric α-synuclein both in vitro and in vivo; ii) identifying the natural kinases and phosphatases responsible for modulating α-synuclein phosphorylation in vivo. These studies provide novel mechanistic insight into the role of phosphorylation at S129 and S87 in the pathogenesis of PD and related synucleinopathies and shed new light on the potential role of phosphorylation in the normal biology of α-syn.