Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy

Intracellular accumulation of filamentous tau aggregates with progressive neuronal
loss is a common characteristic of tauopathies. Although the neurodegenerative
mechanism of tau-associated
pathology remains unclear, molecular elements capable
of degrading and/or sequestering neurotoxic tau species may suppress neurodegenerative
progression. Here, we provide evidence that p62/SQSTM1, a ubiquitinated
cargo receptor for selective autophagy, acts protectively against neuronal death and
neuroinflammation provoked by abnormal tau accumulation. P301S mutant tau transgenic
mice (line PS19) exhibited accumulation of neurofibrillary tangles with localization
of p62 mostly in the brainstem, but neuronal loss with few neurofibrillary tangles
in the hippocampus. In the hippocampus of PS19 mice, the p62 level was lower compared
to the brainstem, and punctate accumulation of phosphorylated tau unaccompanied
by co-localization
of p62 was observed. In PS19 mice deficient in p62 (PS19/
p62-KO),
increased accumulation of phosphorylated tau, acceleration of neuronal
loss, and exacerbation of neuroinflammation were observed in the hippocampus as
compared with PS19 mice. In addition, increase of abnormal tau and neuroinflammation
were observed in the brainstem of PS19/p62-KO.
Immunostaining and dot-blot
analysis with an antibody selectively recognizing tau dimers and higher-order
oligomers
revealed that oligomeric tau species in PS19/p62-KO
mice were significantly accumulated
as compared to PS19 mice, suggesting the requirement of p62 to eliminate
disease-related
oligomeric tau species. Our findings indicated that p62 exerts neuroprotection
against tau pathologies by eliminating neurotoxic tau species, suggesting
that the manipulative p62 and selective autophagy may provide an intrinsic therapy
for the treatment of tauopathy.
K

書誌情報

Aging Cell

p. e13615, 発行日 2022-06

PubMed番号

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PMID

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2023-05-15 16:50:18.700927

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