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.