Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes.

Autor:	Otero MG; Instituto de Biología Celular y Neurociencias, IBCN (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires, CP1121, Argentina., Fernandez Bessone I; Instituto de Biología Celular y Neurociencias, IBCN (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires, CP1121, Argentina., Hallberg AE; Instituto de Biología Celular y Neurociencias, IBCN (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires, CP1121, Argentina., Cromberg LE; Instituto de Biología Celular y Neurociencias, IBCN (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires, CP1121, Argentina., De Rossi MC; Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica-IQUIBICEN UBA-CONICET, Buenos Aires, CP1428EGA, Argentina., Saez TM; Instituto de Biología Celular y Neurociencias, IBCN (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires, CP1121, Argentina.; Instituto de Biología y Medicina Experimental, IBYME (CONICET), Vuelta de obligado 2490, Buenos Aires, CP 1428, Argentina., Levi V; Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica-IQUIBICEN UBA-CONICET, Buenos Aires, CP1428EGA, Argentina., Almenar-Queralt A; Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA., Falzone TL; Instituto de Biología Celular y Neurociencias, IBCN (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires, CP1121, Argentina tfalzone@fmed.uba.ar.; Instituto de Biología y Medicina Experimental, IBYME (CONICET), Vuelta de obligado 2490, Buenos Aires, CP 1428, Argentina.
Jazyk:	angličtina
Zdroj:	Journal of cell science [J Cell Sci] 2018 Jun 11; Vol. 131 (11). Date of Electronic Publication: 2018 Jun 11.
DOI:	10.1242/jcs.214536
Abstrakt:	Alzheimer disease (AD) pathology includes the accumulation of poly-ubiquitylated (also known as poly-ubiquitinated) proteins and failures in proteasome-dependent degradation. Whereas the distribution of proteasomes and its role in synaptic function have been studied, whether proteasome activity regulates the axonal transport and metabolism of the amyloid precursor protein (APP), remains elusive. By using live imaging in primary hippocampal neurons, we showed that proteasome inhibition rapidly and severely impairs the axonal transport of APP. Fluorescence cross-correlation analyses and membrane internalization blockage experiments showed that plasma membrane APP does not contribute to transport defects. Moreover, by western blotting and double-color APP imaging, we demonstrated that proteasome inhibition precludes APP axonal transport by enhancing its endo-lysosomal delivery, where β-cleavage is induced. Taken together, we found that proteasomes control the distal transport of APP and can re-distribute Golgi-derived vesicles to the endo-lysosomal pathway. This crosstalk between proteasomes and lysosomes regulates the intracellular APP dynamics, and defects in proteasome activity can be considered a contributing factor that leads to abnormal APP metabolism in AD.This article has an associated First Person interview with the first author of the paper. Competing Interests: Competing interestsThe authors declare no competing or financial interests. (© 2018. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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