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.

• Abnormal increase in phosphorylation beyond physiological levels.
• Leads to altered protein structure, function, and interactions.
• Often irreversible in pathological states.

• 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.

• Protein misfolding
• Loss of normal function
• Aggregation and toxicity

• Tau hyperphosphorylation → detachment from microtubules
• Aggregation into neurofibrillary tangles
• Driven by overactive CDK5, GSK-3β, and suppressed PP2A

• Oncogenic signaling via hyperphosphorylated proteins
• Altered control of cell cycle and apoptosis

• Parkinson’s disease, frontotemporal dementia, chronic stress response

• 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)

• Tau → Tau-P → Tau-PP → Tau-PPP → Misfolded/aggregated tau

• phosphorylation
• tau protein
• CDK5
• neurofibrillary tangles
• kinase
• phosphatase