MAPK family members differentially regulate pThr175 tau-mediated pathogenicity

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Tau phosphorylation at Thr175 is linked to pathological misfolding and aggregation in tauopathies like CTE and TBI.
• The cellular mechanisms driving Thr175 tau phosphorylation remain poorly understood.
• Oxidative stress and MAPK signaling pathways are implicated in tau phosphorylation.

Purpose of the Study:

• To elucidate the cellular mechanisms responsible for Thr175 tau phosphorylation.
• To identify the specific kinases involved in Thr175 tau phosphorylation.
• To investigate the role of Thr175 tau phosphorylation in initiating pathological tau cascades.

Main Methods:

• Molecular and histological analyses in a rodent model of traumatic brain injury (TBI).
• In vitro kinase assays to assess the phosphorylation of Thr175 tau by candidate kinases.
• Analysis of tau interactions with molecular chaperone DnaJC7.
• Investigation of oxidative stress effects on tau phosphorylation and MAPK signaling.

Main Results:

• ERK2, JNK1, and p38 were identified as candidate kinases associated with pThr175 tau in a TBI model.
• ERK2 and JNK1 were confirmed to phosphorylate Thr175 tau in vitro.
• ERK2-mediated Thr175 tau phosphorylation initiated pathological cascades: PAD exposure, tau oligomerization, truncation, and neurofibrillary tangle formation.
• Thr175 phosphorylation altered tau interaction with DnaJC7, a regulator of tau misfolding.
• Oxidative stress increased pThr175 and pThr231 tau, activating MAPK pathways.

Conclusions:

• ERK2 and JNK1 are key cellular mediators of Thr175 tau phosphorylation.
• ERK2 plays a critical role in initiating pathological tau cascades through Thr175 phosphorylation.
• These findings clarify the upstream mechanisms of pathological tau formation and highlight potential therapeutic targets.