A key to untangling abnormal structures believed to be responsible for the demise of neurons in neurodegenerative diseases may lie in the interaction between two proteins, tau and Pin1.
Alzheimer’s disease (AD) and frontotemporal dementia with parkinsonism-17 (FTDP-17) are two disorders characterized by dementia that share a common abnormality, a brain accumulation of tau proteins in rigid tangles. In healthy neurons, tau binds tubulin with the help of the Pin1 enzyme and promotes microtubule stabilization and assembly. In conditions of tauopathy, hyperphosphorylated tau aggregates in tangles and is incapable of binding microtubules, causing dysfunction and neural loss. Pin1 is important in tauopathy since it can untangle tau by promoting the removal of phosphates. Furthermore, the loss of Pin1 promotes a tanglelike pathology, suggesting Pin levels are important in this neurodegenerative phenotype.
The laboratory of Kun Ping Lu, HMS professor of medicine, sought to determine whether elevating Pin1 levels could prevent neuronal degeneration associated with Alzheimer’s and FTDP-17.
In the May Journal of Clinical Investigation, they report the surprising discovery that Pin1 has diametrically opposite effects on tauopathy in two different experimental mouse models of Alzheimer’s, raising concern over the appropriateness of their use and suggesting the existence of multiple mechanisms for tauopathy generation.
The P301L tau mutation is found in FTDP-17, a relatively rare neurodegenerative disease. It happens to be the preferred Alzheimer’s model, because of the rapid tauopathy generated when it is introduced into mice. However, while tau levels are elevated in AD patients, no tau mutants have been found.
Since loss of Pin1 activity is a major factor contributing to the development of Alzheimer’s, Lu’s lab sought to determine whether Pin1 overexpression could inhibit tau-related neurodegeneration. As expected, Pin1 prevented tau hyperphosphorylation, tau accumulation in tangle complexes, and neural degeneration in wild-type tau transgenic mice.
The investigators were surprised not to get the same results in mice expressing P301L tau. Not only did Pin1 not prevent tauopathy in P301L tau mice, but the condition became worse. When the researchers evaluated Pin1 inhibition in mice expressing wild-type and mutant tau, they again found opposite effects. Pin1 inhibition caused neurodegeneration in transgenic mice expressing wild-type tau, as previously found; however, neurodegeneration was inhibited in the tau mutant mice.
Lu and his colleagues determined that Pin1 controls the stability and accumulation of the tau protein. When Pin1 is present in neuronal cells, tau is degraded, and when Pin1 is removed, tau proteins become stabilized. However, the opposite occurred in neuronal cells expressing the tau P301L mutant; increased tau levels in cells overexpressing Pin exacerbated the tauopathy.
Currently, there is no effective therapy for Alzheimer’s. The use of “overexpression of Pin1 to prevent neurodegeneration is quite exciting,” said Lu. “We don’t know why the tau mutant caused such an aggressive change, but it raises serious questions about the models for AD that are used.” While the P301L tau mutation doesn’t represent Alzheimer’s, the conclusions made from studies with these mice are useful for FTDP-17.
