Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P10636 (
tau protein
)
5,110
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Missorting of
MAPT
/Tau represents one of the early signs of neurodegeneration in Alzheimer disease. The triggers for this are still a matter of debate. Here we investigated the sorting mechanisms of endogenous
MAPT
in mature primary neurons using microfluidic chambers (MFCs) where cell compartments can be observed separately. Blocking protein degradation pathways with proteasomal or autophagy inhibitors dramatically increased the missorting of
MAPT
in dendrites on the neuritic side, suggesting that degradation of
MAPT
in dendrites is a major determinant for the physiological axonal distribution of
MAPT
. Such missorted dendritic
MAPT
differed in its phosphorylation pattern from axonal
MAPT
. By contrast, enhancing autophagy or proteasomal pathways strongly reduced
MAPT
missorting, thereby confirming the role of protein degradation pathways in the polar distribution of
MAPT
. Dendritic missorting of
MAPT
by blocking protein degradation resulted in the loss of spines but not in overall cell toxicity. Inhibition of local protein synthesis in dendrites eliminated the missorting of
MAPT
, indicating that the accumulation of dendritic
MAPT
is locally generated. In support of this, a substantial fraction of Mapt/Tau mRNA was detected in dendrites. Taken together, our results indicate that the autophagy and proteasomal pathways play important roles in fine-tuning dendritic
MAPT
levels and thereby prevent synaptic toxicity caused by
MAPT
accumulation. Abbreviations Ani: anisomycin; Baf: bafilomycin A
1
; BSA: bovine serum albumin; cAMP: cyclic adenosine monophosphate; CHX: cycloheximide; DMSO: dimethyl sulfoxide; DIV: days in vitro; Epo: epoxomicin; E18: embryonic day 18; FISH: fluorescence in situ hybridization; IgG: immunoglobulin; kDa: kilodalton;
Lac
: lactacystin; LDH: lactate dehydrogenase; MFC: microfluidic chambers; MAPs: microtubule-associated proteins;
MAPT
/Tau:
microtubule-associated protein tau
; PVDF: polyvinylidene difluoride; PBS: phosphate-buffered saline; PRKA: protein kinase AMP-activated; RD150: round device 150; RT: room temperature; SDS: sodium dodecyl sulfate; SEM: standard error of the mean; Wor: wortmannin.
...
PMID:Pathological missorting of endogenous MAPT/Tau in neurons caused by failure of protein degradation systems. 3014 31
