Regulation of Protein Conformation by Pin1 Offers Novel Disease Mechanisms and Therapeutic Approaches in Alzheimer's Disease

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 A beta 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.