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Ser46-Phosphorylated MARCKS Is a Marker of Neurite Degeneration at the Pre-aggregation Stage in PD/DLB Pathology

Kyota Fujita1, Hidenori Homma1, Kanoh Kondo1

  • 1Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Eneuro
|September 19, 2018
PubMed

Insights

Early-stage Alzheimer

Area of Science:

  • Neuroscience
  • Neuropathology
  • Molecular Biology

Background:

  • Phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) is an early indicator of neurite degeneration in Alzheimer's disease (AD).
  • This degeneration occurs before extracellular amyloid-beta (Aβ) aggregates are detectable.
  • A common mechanism for pre-aggregation neurite degeneration may exist across neurodegenerative diseases.

Purpose of the Study:

  • To investigate if similar MARCKS phosphorylation changes occur in Parkinson's disease (PD) and dementia with Lewy bodies (DLB).
  • To determine the temporal relationship between MARCKS phosphorylation and alpha-synuclein aggregation in PD/DLB models.
  • To explore a potential shared pathway in early neurodegeneration.

Main Methods:

  • Analysis of MARCKS phosphorylation levels in mouse models of PD/DLB and human postmortem brain tissues.
  • Correlation of pSer46-MARCKS levels with the presence and stage of alpha-synuclein aggregation.
  • Assessment of MARCKS changes in asymptomatic mouse models.

Main Results:

  • Increased levels of phosphorylated MARCKS (pSer46-MARCKS) were observed in mouse models and human patients with PD and DLB.
  • Elevated pSer46-MARCKS preceded alpha-synuclein aggregate formation in asymptomatic mouse models.
  • These changes were sustained during aging and consistent with human brain pathology.

Conclusions:

  • MARCKS phosphorylation is a conserved early event in neurite degeneration across AD, PD, and DLB.
  • This finding suggests a common pre-aggregation mechanism contributing to neurodegeneration in these distinct pathologies.
  • MARCKS phosphorylation may serve as a potential early biomarker for multiple neurodegenerative diseases.
Keywords:
BiomarkerMARCKSdegenerationneuritephosphorylation

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