====== Hyperphosphorylation ====== **Hyperphosphorylation** is a pathological process in which **excessive phosphate groups** are added to a protein, typically at serine, threonine, or tyrosine residues. It is often due to an **imbalance between kinase and phosphatase activities**. ===== Definition ===== * Abnormal increase in phosphorylation beyond physiological levels. * Leads to altered protein structure, function, and interactions. * Often irreversible in pathological states. ===== Mechanism ===== * Protein kinases (e.g., CDK5, GSK-3β, AMPK) add phosphate groups. * Protein phosphatases (e.g., PP2A) remove them. * In disease states, kinase activity is upregulated or phosphatase activity is suppressed. ===== Pathological Consequences ===== * Protein misfolding * Loss of normal function * Aggregation and toxicity ===== Clinical Relevance ===== ==== Alzheimer’s Disease ==== * **Tau hyperphosphorylation** → detachment from microtubules * Aggregation into **neurofibrillary tangles** * Driven by overactive CDK5, GSK-3β, and suppressed PP2A ==== Cancer ==== * Oncogenic signaling via hyperphosphorylated proteins * Altered control of cell cycle and apoptosis ==== Other Disorders ==== * Parkinson’s disease, frontotemporal dementia, chronic stress response ===== Therapeutic Strategies ===== * **Kinase inhibitors** (e.g., CDK5 or AMPK blockers) * **Phosphatase activators** * **Immunotherapies** targeting hyperphosphorylated epitopes * **Receptor modulation** (e.g., δ-opioid receptor pathways to inhibit tau phosphorylation) ===== Example ===== * Tau → Tau-P → Tau-PP → Tau-PPP → Misfolded/aggregated tau ===== Related Concepts ===== * [[phosphorylation]] * [[tau protein]] * [[CDK5]] * [[neurofibrillary tangles]] * [[kinase]] * [[phosphatase]]