Xiao Zhen Zhou

The unique prolyl isomerase Pin1 binds to and catalyzes cis–trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation, thereby playing a pivotal role in regulating the structure and function of its protein substrates. In particular, Pin1 activity regulates the affinity of a substrate for E3 ubiquitin ligases, thereby modulating the turnover of a subset of proteins and coordinating their activities after phosphorylation in both physiological and disease states. In this review, we highlight recent advancements in Pin1-regulated ubiquitination in the context of cancer and neurodegenerative disease. Specifically, Pin1 promotes cancer progression by increasing the stabilities of numerous oncoproteins and decreasing the stabilities of many tumor suppressors. Meanwhile, Pin1 plays a critical role in different neurodegenerative disorders via the regulation of protein turnover. Finally, we propose a novel therapeutic approach wherein the ubiquitin–proteasome system can be leveraged for therapy by targeting pathogenic intracellular targets for TRIM21-dependent degradation using stereospecific antibodies.

Conventional tauopathies are a group of disease characterized by tau inclusions in the brains, including Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and certain types of frontotemporal dementia (FTD), among which AD is the most prevalent. Extensive post‐translational modifications, especially hyperphosphorylation, and abnormal aggregation of tau protein underlie tauopathy. Cis–trans isomerization of protein plays an important role in protein folding, function, and degradation, which is regulated by peptidyl‐proline isomerases (PPIases). Peptidyl‐prolyl cis–trans isomerase NIMA‐interacting 1 (Pin1), the only PPIase found to isomerize Pro following phosphorylated Ser or Thr residues, alters phosphorylated tau protein conformation at pT231‐P motif. The cis P‐tau but not trans P‐tau serves as an early driver of multiple neurodegenerative disease, encompassing AD, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), and vascular contributions to cognitive impairment and dementia (VCID). Cis but not trans P‐tau is resistant to protein dephosphorylation and degradation, and also prone to protein aggregation. Cis P‐tau loses its ability to stabilize microtubule, causing and spreading tauopathy mainly in axons, a pathological process called cistauosis. The conformation‐specific monoclonal antibody that targets only the cis P‐tau serves as a very early diagnosis method and a potential treatment of not only conventional tauopathies but also nonconventional tauopathies such as VCID, with clinical trials ongoing. Notably, cis P‐tau antibody is the only clinical‐stage Alzheimer's therapeutic that has shown the efficacy in animal models of not only AD but also TBI and stroke, which are very early stages of dementia. Here we review the identification and pathological consequences of cis pt231‐tau, the role of its regulator Pin1, as well as the clinical implication of cis pt231‐tau conformation‐specific antibody in conventional and nonconventional tauopathies. image