Mitogen-Activated Protein Kinase Pathways in Neurodegenerative Disorders

Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signal transduction pathways that relay extracellular and intracellular stress cues to diverse cellular outcomes. Three major MAPK modules—extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK—are activated sequentially by phosphorylation events and regulate neuronal survival, synaptic plasticity, inflammation and apoptosis. In the ageing brain and in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis, aberrant MAPK activation contributes to pathological processes including tau hyperphosphorylation, amyloid-β generation, oxidative stress, microglial activation and excitotoxicity. Cross-talk between glial and neuronal MAPK signalling modulates cytokine release, synaptic strength and protein homeostasis. Inhibition or selective modulation of specific MAPK isoforms has emerged as a promising therapeutic approach to restore homeostatic signalling, attenuate neuroinflammatory cascades and protect synaptic function.

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Mitogen-Activated Protein Kinase Pathways in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in mitogen-activated protein kinase pathways in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

MAPK: A family of serine/threonine kinases that transduce extracellular signals into intracellular responses via phosphorylation cascades.

p38 MAPK: A stress-activated MAPK isoform that regulates inflammatory responses, apoptosis and tau phosphorylation in neurodegeneration.

Phosphorylation: The enzymatic addition of a phosphate group to a protein or lipid, modulating its activity, stability or cellular localisation.

Protein degradation (TPD): A therapeutic strategy using bifunctional molecules to tag specific phosphorylated or mutated proteins for ubiquitin-proteasome–mediated clearance.

Synaptic plasticity: The capacity of synapses to strengthen or weaken over time in response to activity, essential for learning and memory.

References

1. Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease. Pharmacology & Therapeutics (2024).
2. Chemical Knockdown of Phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK) as a Novel Approach for the Treatment of Alzheimer′s Disease. ACS Central Science (2023).
3. A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse. Alzheimer's Research & Therapy (2020).