Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=24337465
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Nilotinib-induced autophagic changes increase endogenous parkin level and
ubiquitination, leading to amyloid clearance
#MMPMID24337465
Lonskaya I
; Hebron ML
; Desforges NM
; Schachter JB
; Moussa CE
J Mol Med (Berl)
2014[Apr]; 92
(4
): 373-86
PMID24337465
show ga
Alzheimer's disease (AD) is a neurodegenerative disorder associated with amyloid
accumulation and autophagic changes. Parkin is an E3 ubiquitin ligase involved in
proteasomal and autophagic clearance. We previously demonstrated decreased parkin
solubility and interaction with the key autophagy enzyme beclin-1 in AD, but
tyrosine kinase inhibition restored parkin-beclin-1 interaction. In the current
studies, we determined the mechanisms of nilotinib-induced parkin-beclin-1
interaction, which leads to amyloid clearance. Nilotinib increased endogenous
parkin levels and ubiquitination, which may enhance parkin recycling via the
proteasome, leading to increased activity and interaction with beclin-1. Parkin
solubility was decreased and autophagy was altered in amyloid expressing mice,
suggesting that amyloid stress affects parkin stability, leading to failure of
protein clearance via the lysosome. Isolation of autophagic vacuoles revealed
amyloid and parkin accumulation in autophagic compartments but nilotinib
decreased insoluble parkin levels and facilitated amyloid deposition into
lysosomes in wild type, but not parkin(-/-) mice, further underscoring an
essential role for endogenous parkin in amyloid clearance. These results suggest
that nilotinib boosts the autophagic machinery, leading to increased level of
endogenous parkin that undergoes ubiquitination and interacts with beclin-1 to
facilitate amyloid clearance. These data suggest that nilotinib-mediated
autophagic changes may trigger parkin response via increased protein levels,
providing a therapeutic strategy to reduce A? and Tau in AD. KEY MESSAGE: Parkin
solubility (stability) is decreased in AD and APP transgenic mice.
Nilotinib-induced autophagic changes increase endogenous parkin level. Increased
parkin level leads to ubiquitination and proteasomal recycling. Re-cycling
decreases insoluble parkin and increases parkin-beclin-1 interaction.
Beclin-1-parkin interaction enhances amyloid clearance.
free
free
free
