Tau Conformation in Tauopathies and Neuronal Function

Misfolded and hyperphosphorylated tau are hallmarks of the tauopathies, including Alzheimer’s disease (AD)
and Related Dementias (ADRDs), such as Progressive Supranuclear Palsy, Cortical Basal Degeneration, Pick’s
disease, Frontotemporal Dementias and Chronic Traumatic Encephalopathy (CTE), among others. To
understand these diseases, we need to know what makes pathological tau toxic and how this relates to normal
functions of tau. Our central hypothesis is that pathogenic forms of tau represent misregulation of a normal
biological function for tau as a scaffold for localization and regulation of multiple kinases and phosphatases. Our
discovery of a biologically active motif in tau (called the Phosphatase Activating Domain, PAD) that activates
protein phosphatase 1 (PP1) and glycogen synthase kinase 3b (GSK3b) provided a common molecular basis
for increased kinase activities in tauopathies and supports the contention that tau acts as a scaffolding protein
to regulate signaling pathways. This function is disrupted by disease-related tau changes. Exposure of PAD is
normally carefully regulated and transient but becomes constitutively exposed in pathological tau. Recent studies
show that specific pathological forms of tau also activate casein kinase 2 (CK2) and c-Jun N-terminal kinase
(JNK) pathways, which represent novel mechanisms that are a central focus of this proposal. We propose that
toxicity of pathological tau may be modulated by disease-specific patterns of tau posttranslational modifications
(PTMs), isoforms and mutations that affect tau conformation and lead to disruption of neuronal functions via
dysregulated CK2 and JNK signaling. Aim 1 will define effects of tau PTMs on tau function and pathology.
In addition to multiple phosphorylation sites, several other tau PTMs are known, including acetylation, cross-
linking and polyamination, among others. We will evaluate the effects of PTMs (single sites and combinations of
sites) on presentation of PAD and SH3-binding domains that affect CK2, JNK and PP1/GSK3b signaling
pathways regulated by tau. Aim 2 will determine the role of disease-related forms of tau using models of
sporadic and inherited tauopathy. We will evaluate how mutations in tau may lead to differential exposure of
PAD and SH3-binding domains to dysregulate CK2, JNK and PP1/GSK3b pathways. Aim 3 will identify
molecular mechanisms for tau-mediated activation of novel neuronal signaling pathways. We will
characterize the mechanisms underlying tau-mediated regulation of CK2 and JNK pathways by manipulating
motifs in each protein and using a host of biochemical and in-cell protein-protein interaction assays. Aim 4 will
define physiological roles for tau in developing and mature neurons. We will evaluate how regulation of tau
isoforms and PTMs play critical roles in neuronal development as well as pathogenesis in AD and ADRDs.
These studies will have significant impact by identifying novel mechanisms regulating exposure of biologically
active motifs involved in tau’s role as a scaffolding protein that regulates signaling pathways critical for neuronal
function and that are disrupted by disease-associated aggregation, PTMs and mutations.

Grant Number: 2RF1NS082730-11A1
NIH Institute/Center: NIH
Principal Investigator: SCOTT BRADY