Reciprocal effects of alpha-synuclein overexpression and proteasome inhibition in neuronal cells and tissue - PubMed (original) (raw)
Reciprocal effects of alpha-synuclein overexpression and proteasome inhibition in neuronal cells and tissue
Melanie Dyllick-Brenzinger et al. Neurotox Res. 2010 Apr.
Abstract
Defects in the 20S/26S proteasome and conformational changes in alpha-synuclein (alpha-syn) are implicated in the development of sporadic and familial cases of PD. The objective of this study was to evaluate whether alpha-syn affects proteolysis by the proteasome and, reciprocally, whether proteasome inhibition affects alpha-syn solubility and localization. Although alpha-syn directly inhibited purified 20S proteasomes reversibly in vitro, its overexpression in neuroblastoma (SH-SY5Y and SK-N-BE), embryonic kidney (HEK293) cells, or mouse brain did not affect proteasome activity. Proteasome inhibition with MG132 and epoxomicin in SH-SY5Y cells failed to induce alpha-syn aggregation, although it increased membrane bound forms of endogenous and overexpressed wild-type, but not mutant, alpha-syn. Concomitantly this treatment generated cytoplasmic alpha-syn inclusions devoid of polyubiquitin in a small percentage of cells. The combination of proteasome inhibition with serum deprivation, which induced oxidative stress and autophagy, caused the appearance of high molecular weight alpha-syn species, such as those found in Lewy bodies. Our data suggest that high concentrations of alpha-syn do not affect proteasome function in vivo, whereas proteasome inhibition can modify synuclein solubility, most prominently under conditions of cell stress which occur during aging. These results have implications for the convergence of age-related oxidative stress and impaired protein degradation in neurodegeneration.
Similar articles
- Inhibition of FK506 binding proteins reduces alpha-synuclein aggregation and Parkinson's disease-like pathology.
Gerard M, Deleersnijder A, Daniëls V, Schreurs S, Munck S, Reumers V, Pottel H, Engelborghs Y, Van den Haute C, Taymans JM, Debyser Z, Baekelandt V. Gerard M, et al. J Neurosci. 2010 Feb 17;30(7):2454-63. doi: 10.1523/JNEUROSCI.5983-09.2010. J Neurosci. 2010. PMID: 20164329 Free PMC article. - alpha-Synuclein expression levels do not significantly affect proteasome function and expression in mice and stably transfected PC12 cell lines.
Martìn-Clemente B, Alvarez-Castelao B, Mayo I, Sierra AB, Dìaz V, Milán M, Fariñas I, Gómez-Isla T, Ferrer I, Castaño JG. Martìn-Clemente B, et al. J Biol Chem. 2004 Dec 17;279(51):52984-90. doi: 10.1074/jbc.M409028200. Epub 2004 Oct 4. J Biol Chem. 2004. PMID: 15466467 - Accelerated formation of alpha-synuclein oligomers by concerted action of the 20S proteasome and familial Parkinson mutations.
Lewis KA, Yaeger A, DeMartino GN, Thomas PJ. Lewis KA, et al. J Bioenerg Biomembr. 2010 Feb;42(1):85-95. doi: 10.1007/s10863-009-9258-y. Epub 2010 Feb 11. J Bioenerg Biomembr. 2010. PMID: 20148295 Free PMC article. - Distinct alpha-Synuclein species induced by seeding are selectively cleared by the Lysosome or the Proteasome in neuronally differentiated SH-SY5Y cells.
Pantazopoulou M, Brembati V, Kanellidi A, Bousset L, Melki R, Stefanis L. Pantazopoulou M, et al. J Neurochem. 2021 Mar;156(6):880-896. doi: 10.1111/jnc.15174. Epub 2020 Sep 22. J Neurochem. 2021. PMID: 32869336 - The good and bad of therapeutic strategies that directly target α-synuclein.
Longhena F, Faustini G, Brembati V, Pizzi M, Bellucci A. Longhena F, et al. IUBMB Life. 2020 Apr;72(4):590-600. doi: 10.1002/iub.2194. Epub 2019 Nov 6. IUBMB Life. 2020. PMID: 31693290 Review.
Cited by
- Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is Associated with Cognitive Impairment in Lewy Body Dementia.
Alghamdi A, Vallortigara J, Howlett DR, Broadstock M, Hortobágyi T, Ballard C, Thomas AJ, O'Brien JT, Aarsland D, Attems J, Francis PT, Whitfield DR. Alghamdi A, et al. J Alzheimers Dis. 2017;57(2):373-386. doi: 10.3233/JAD-160946. J Alzheimers Dis. 2017. PMID: 28269775 Free PMC article. - Effect of Ser-129 phosphorylation on interaction of α-synuclein with synaptic and cellular membranes.
Visanji NP, Wislet-Gendebien S, Oschipok LW, Zhang G, Aubert I, Fraser PE, Tandon A. Visanji NP, et al. J Biol Chem. 2011 Oct 14;286(41):35863-35873. doi: 10.1074/jbc.M111.253450. Epub 2011 Aug 17. J Biol Chem. 2011. PMID: 21849493 Free PMC article. Retracted. - The extent of neurodegeneration and neuroprotection in two chemical in vitro models related to Parkinson's disease is critically dependent on cell culture conditions.
Jantas D, Roman A, Kuśmierczyk J, Lorenc-Koci E, Konieczny J, Lenda T, Lasoń W. Jantas D, et al. Neurotox Res. 2013 Jul;24(1):41-54. doi: 10.1007/s12640-012-9374-z. Epub 2013 Jan 10. Neurotox Res. 2013. PMID: 23307753 - The Proteasome Inhibition Model of Parkinson's Disease.
Bentea E, Verbruggen L, Massie A. Bentea E, et al. J Parkinsons Dis. 2017;7(1):31-63. doi: 10.3233/JPD-160921. J Parkinsons Dis. 2017. PMID: 27802243 Free PMC article. Review. - Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein.
McKinnon C, De Snoo ML, Gondard E, Neudorfer C, Chau H, Ngana SG, O'Hara DM, Brotchie JM, Koprich JB, Lozano AM, Kalia LV, Kalia SK. McKinnon C, et al. Acta Neuropathol Commun. 2020 Feb 14;8(1):17. doi: 10.1186/s40478-020-0894-0. Acta Neuropathol Commun. 2020. PMID: 32059750 Free PMC article.
References
- J Neurochem. 2003 Sep;86(5):1297-307 - PubMed
- Annu Rev Biochem. 2005;74:29-52 - PubMed
- J Biol Chem. 2000 Jun 16;275(24):18344-9 - PubMed
- J Neurochem. 2000 Nov;75(5):2221-4 - PubMed
- Nature. 1997 Aug 28;388(6645):839-40 - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous