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Science Forum Index » Life Extension Forum » Proteasomal inhibition by a-synuclein; reversal by HSP-70
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| kofi |
 Posted: Fri Jan 09, 2004 7:08 pm |
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Another reason not to mix proteasomal inihibitors and neurodegeneration.
J Biol Chem. 2004 Jan 7 [Epub ahead of print]. Links
Click here to read
Proteasomal inhibition by alpha -synuclein filaments and oligomers.
Lindersson E, Beedholm R, Hojrup P, Moos T, Gai W, Hendil KB, Jensen
PH.
Department of Medical Biochemistry, University of Aarhus, Aarhus-C,
Aarhus DK-8000.
A unifying feature of many neurodegenerative disorders is the
accumulation of poly-ubiquitinated protein inclusions in dystrophic
neurons, e.g. containing a-synuclein, which is suggestive of an
insufficient proteasomal activity. We demonstrate that a-synuclein and
20S proteasom components co-localise in Lewy bodies and show that
subunits from 20S proteasome particles, in contrast to subunits of the
19S regulatory complex, bind efficiently to aggregated filamentous but
not monomeric a-synuclein. Proteasome binding to insoluble a-synuclein
filaments and soluble a-synuclein oligomers result in marked inhibition
of its chymotrypsin-like hydrolytic activity through a non-competitive
mechanism that is mimicked by model amyloid-Ab peptide aggregates.
Endogenous ligands of aggregated a-synuclein like heat shock protein 70
and glyceraldehyde-3-phosphate dehydrogenase bind filaments and inhibit
their anti-proteasomal activity. The inhibitory of amyloid aggregates
may thus be amenable to modulation by endogenous chaperones, and
possibly accessible for therapeutic intervention
PMID: 14711827 [PubMed - as supplied by publisher] |
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