Pinning down phosphorylated tau and tauopathies

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Neurofibrillary tangles (NFTs), composed of hyperphosphorylated Tau, are hallmarks of neurodegenerative diseases like Alzheimer's disease (AD).
• The regulation of Tau following phosphorylation remains poorly understood.
• Phosphorylated serine/threonine-proline (pSer/Thr-Pro) motifs in Tau exist in distinct conformations.

Purpose of the Study:

• To investigate the role of prolyl isomerase Pin1 in regulating Tau conformation and its impact on neurodegeneration.
• To explore Pin1 as a potential therapeutic target for neurodegenerative diseases.

Main Methods:

• Investigated Pin1 binding to phosphorylated Tau.
• Analyzed the effect of Pin1 on Tau conformation, microtubule binding, and dephosphorylation.
• Correlated Pin1 expression with neuronal vulnerability and neurofibrillary degeneration in AD brain.
• Studied the effects of Pin1 gene deletion in mice on neurodegeneration and Tau pathology.

Main Results:

• Pin1 binds to Tau phosphorylated at Thr231-Pro, catalyzing cis/trans isomerization and inducing conformational changes.
• These conformational changes restore Tau's ability to bind microtubules and facilitate dephosphorylation by PP2A.
• Pin1 expression inversely correlates with neuronal vulnerability and AD neurofibrillary degeneration.
• Pin1 gene deletion in mice leads to age-dependent neuropathy, Tau hyperphosphorylation, filament formation, and neuronal degeneration.

Conclusions:

• Pin1 plays a pivotal role in maintaining normal neuronal function by regulating Tau conformation.
• Pin1 deficiency causes age-dependent neurodegeneration and Tau pathologies, distinct from other models.
• Pin1 represents a promising therapeutic target for preventing neurodegenerative diseases.