Hyperphosphorylation [Neurosurgery Wiki]

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====== 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]]