Regenerating islet-derived 1α (REG-1α) protein increases tau phosphorylation in cell and animal models of tauopathies

Moussaed, M., Huc-Brandt, S., Cubedo, N., Silhol, M., Murat, S., Lebart, M.C., Kovacs, G., Verdier, J.M., Trousse, F., Rossel, M., Marcilhac, A.
Neurobiology of disease   119: 136-148 (Journal)
Registered Authors
Cubedo, Nicolas, Rossel, Mireille
Cortical neurons, GSK-3β, Human brain, Phosphorylation, REG-1α, Tau, Zebrafish
MeSH Terms
  • Aged
  • Aged, 80 and over
  • Animals
  • Animals, Genetically Modified
  • Brain/metabolism
  • Brain/pathology
  • Cells, Cultured
  • Disease Models, Animal*
  • Female
  • Humans
  • Lithostathine/biosynthesis*
  • Lithostathine/genetics
  • Male
  • Middle Aged
  • Phosphorylation/physiology
  • Rats
  • Tauopathies/genetics
  • Tauopathies/metabolism*
  • Tauopathies/pathology
  • Zebrafish
  • tau Proteins/biosynthesis*
  • tau Proteins/genetics
30092268 Full text @ Neurobiol. Dis.
REG-1α, a secreted protein containing a C-type lectin domain, is expressed in various organs and plays different roles in digestive system cells in physiological and pathological conditions. Like other members of the Reg family, REG-1α is expressed also in the brain where it has different functions. For instance, we previously reported that REG-1α regulates neurite outgrowth and is overexpressed during the very early stages of Alzheimer's disease (AD). However, REG-1α function in neural cells during neural degeneration remains unknown. First, REG-1α and phosphorylated tau expression were assessed in tissue sections from the hippocampus, representing neurofibrillary tangles (NFTs), from patients with AD, and from basal ganglia, representing subcortical NFTs, from patients with progressive supranuclear palsy (PSP). We found an association between REG-1α expression, tau hyperphosphorylation and NFTs in human brain samples from patients with these neurodegenerative diseases. Then, the effects of REG-1α overexpression on tau phosphorylation and axonal morphology were investigated i) in primary cultures of rat neurons that express human tau P301L and ii) in a transgenic zebrafish model of tauopathy that expresses human tau P301L. In the tau P301L cell model, REG-1α overexpression increased tau phosphorylation at the S202/T205 and S396 residues (early and late stages of abnormal phosphorylation, respectively) through the AKT/GSK3-β pathway. This effect was associated with axonal defects both in tau P301L-expressing rat neurons and zebrafish embryos. Our findings suggest a functional role for REG-1α during tauopathy development and progression and, specifically, its involvement in the modification of tau phosphorylation temporal sequence.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes