A selective degeneration of cholinergic neurons mediated by NRADD in an Alzheimer's disease mouse model.

Cholinergic neurons in the basal forebrain constitute a major source of cholinergic inputs to the forebrain, modulate diverse functions including sensory processing, memory and attention, and are vulnerable to Alzheimer's disease (AD). Recently, we classified cholinergic neurons into two distinct subpopulations; calbindin D28K-expressing (D28K+) versus D28K-lacking (D28K-) neurons. Yet, which of these two cholinergic subpopulations are selectively degenerated in AD and the molecular mechanisms underlying this selective degeneration remain unknown. Here, we reported a discovery that D28K+ neurons are selectively degenerated and this degeneration induces anxiety-like behaviors in the early stage of AD. Neuronal type specific deletion of NRADD effectively rescues D28K+ neuronal degeneration, whereas genetic introduction of exogenous NRADD causes D28K- neuronal loss. This gain- and loss-of-function study reveals a subtype specific degeneration of cholinergic neurons in the disease progression of AD and hence warrants a novel molecular target for AD therapy.

Nradd Acts as a Negative Feedback Regulator of Wnt/ß-Catenin Signaling and Promotes Apoptosis.

Wnt/ß-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases entails detailed understanding of the regulatory mechanisms that fine-tune Wnt signaling. Here, we identify the neurotrophin receptor-associated death domain (Nradd), a homolog of p75 neurotrophin receptor (p75NTR), as a negative regulator of Wnt/ß-catenin signaling in zebrafish embryos and in mammalian cells. Nradd significantly suppresses Wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Nradd is localized at the plasma membrane, physically interacts with the Wnt receptor complex and enhances apoptosis in cooperation with Wnt/ß-catenin signaling. Our functional analyses indicate that the N-glycosylated N-terminus and the death domain-containing C-terminus regions are necessary for both the inhibition of Wnt signaling and apoptosis. Finally, Nradd can induce apoptosis in mammalian cells. Thus, Nradd regulates cell death as a modifier of Wnt/ß-catenin signaling during development.

NMR structure of a full-length single-pass membrane protein NRADD.

Structural study of any single-pass membrane protein is both an important and challenging task. In this report, we present the structure of a neurotrophin receptor-alike death-domain protein. The structure and dynamics of the protein was investigated by conventional nuclear magnetic resonance techniques in the solution of phospholipid bicelles. The receptor contains two folded regions-α-helical transmembrane domain and globular C-terminal death domain with more than 50% of the rest of backbone being disordered. This is the first structure of a full-length single-pass membrane receptor-alike protein solved by the single method.