Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity...

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Abnormal tau phosphorylation is a hallmark of neurodegenerative diseases like Alzheimer's disease (AD).
• PAR-1/MARK kinase phosphorylates tau at Ser262 and Ser356, initially stabilizing it during mismetabolism.
• The distinct roles of Ser262 and Ser356 phosphorylation in tau stabilization remain unclear.

Purpose of the Study:

• To investigate the differential contribution of tau phosphorylation at Ser262 and Ser356 to tau stabilization.
• To elucidate the role of PAR-1/MARK in tau phosphorylation and its impact on tau levels in vivo.
• To understand the mechanisms underlying tau pathology in neurodegenerative conditions.

Main Methods:

• Utilized a Drosophila model expressing human tau.
• Manipulated phosphorylation at tau Ser262 and Ser356 residues.
• Assessed total tau levels and phosphorylation status under varying PAR-1/MARK activity.

Main Results:

• Tau phosphorylation occurred at Ser262 but not Ser356 in the absence of PAR-1/MARK overexpression.
• Blocking Ser262 phosphorylation reduced total tau levels.
• Co-overexpression of PAR-1/MARK with tau led to hyperphosphorylation at both Ser262 and Ser356, significantly increasing tau protein levels.
• Preventing phosphorylation at both sites was required to fully suppress the tau elevation.

Conclusions:

• Tau phosphorylation at Ser262 is the primary driver of tau stabilization under normal PAR-1/MARK activity.
• Ser356 phosphorylation contributes to tau stabilization and accumulation when PAR-1/MARK activity is abnormally high, as observed in diseased brains.
• These findings offer insights into the differential regulation of tau pathology in neurodegenerative diseases.