Work

Regulation of protein conformation by Pin1 offers novel disease mechanisms and therapeutic approaches in Alzheimer's disease.

Year: 2014

Type: review

Abstract: Pin1 is a unique enzyme that changes the shape of target proteins by acting on specific amino acids that have been phosphorylated: serine or threonine residues that precede proline. Pin1 catalyzes the flip between two distinct orientations, called cis and trans, around the proline bond. This change in shape has profound effects on protein function and is a major signaling mechanism in the cell. Abnormal regulation of Pin1 has been associated with premature aging and multiple pathological processes, notably cancer and Alzheimer's disease (AD), two major age-related diseases. In AD, Pin1 affects two proteins thought to be key to disease pathology: the amyloid precursor protein (APP) and the microtubule-binding protein tau, by switching them from a dysfunctional shape (cis) back to a functional one (trans), which can be distinguished by cis and trans-specific antibodies. In the brains of people with AD, Pin1 is absent or inactivated and cis tau is accumulated at early stages of AD. In the absence of Pin1, APP is processed into toxic beta-amyloid and tau becomes misshapen to form tangles. As a result, Pin1-deficient mice develop age-dependent tau and Aβ pathologies and neuronal degeneration and loss. Thus, regulation of protein conformation by Pin1 has a critical neuroprotective role and offers a novel diagnostic and therapeutic target for AD. Notably, antibodies or vaccines specifically against the dysfunctional misshapen tau (while leaving the functional one untouched) may offer early diagnosis and treatment of AD and related disorders.

Source: PubMed

Authors: Jane A Driver, Xiao Zhen Zhou, Kun Ping Lu

Institutions: Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard University, VA Boston Healthcare System

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institute on Aging, National Heart, Lung, and Blood Institute, National Cancer Institute

Awards: Function and Regulation of the Phosphorylation-Specific Prolyl Isomerase Pin1, Role of the Prolyl Isomerase Pin1 in the Development and Treatment of Asthma, Drug Discovery against the Early, Secreted and Toxic Tau in Alzheimer's Disease, Pin1-Catalyzed Protein Conformational Regulation in Alzheimer's Disease