Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes
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 regu...
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2018
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219533_v131_n11_p_Otero http://hdl.handle.net/20.500.12110/paper_00219533_v131_n11_p_Otero |
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paper:paper_00219533_v131_n11_p_Otero2023-06-08T14:43:46Z Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes Alzheimer disease Amyloid precursor protein Axonal transport Lysosome Proteasome amyloid precursor protein proteasome animal cell animal tissue Article cell membrane controlled study fluorescence analysis Golgi complex hippocampus live cell imaging lysosome molecular interaction mouse nerve cell nerve fiber transport newborn nonhuman priority journal protein aggregation protein degradation protein localization protein metabolism protein processing protein transport Western blotting 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 andmembrane 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. © 2018. Published by The Company of Biologists Ltd. 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219533_v131_n11_p_Otero http://hdl.handle.net/20.500.12110/paper_00219533_v131_n11_p_Otero |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Alzheimer disease Amyloid precursor protein Axonal transport Lysosome Proteasome amyloid precursor protein proteasome animal cell animal tissue Article cell membrane controlled study fluorescence analysis Golgi complex hippocampus live cell imaging lysosome molecular interaction mouse nerve cell nerve fiber transport newborn nonhuman priority journal protein aggregation protein degradation protein localization protein metabolism protein processing protein transport Western blotting |
| spellingShingle |
Alzheimer disease Amyloid precursor protein Axonal transport Lysosome Proteasome amyloid precursor protein proteasome animal cell animal tissue Article cell membrane controlled study fluorescence analysis Golgi complex hippocampus live cell imaging lysosome molecular interaction mouse nerve cell nerve fiber transport newborn nonhuman priority journal protein aggregation protein degradation protein localization protein metabolism protein processing protein transport Western blotting Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes |
| topic_facet |
Alzheimer disease Amyloid precursor protein Axonal transport Lysosome Proteasome amyloid precursor protein proteasome animal cell animal tissue Article cell membrane controlled study fluorescence analysis Golgi complex hippocampus live cell imaging lysosome molecular interaction mouse nerve cell nerve fiber transport newborn nonhuman priority journal protein aggregation protein degradation protein localization protein metabolism protein processing protein transport Western blotting |
| description |
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 andmembrane 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. © 2018. Published by The Company of Biologists Ltd. |
| title |
Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes |
| title_short |
Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes |
| title_full |
Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes |
| title_fullStr |
Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes |
| title_full_unstemmed |
Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes |
| title_sort |
proteasome stress leads to app axonal transport defects by promoting its amyloidogenic processing in lysosomes |
| publishDate |
2018 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219533_v131_n11_p_Otero http://hdl.handle.net/20.500.12110/paper_00219533_v131_n11_p_Otero |
| _version_ |
1768544987270610944 |