Impaired axonal retrograde trafficking of the retromer complex augments lysosomal deficits in Alzheimer’s disease neurons
| Autor: | Yu Young Jeong, Daniyal Aikal, Prasad Tammineni, Qian Cai, Tuancheng Feng |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Retromer Endosome Vesicular Transport Proteins Golgi Apparatus Cellular homeostasis Mice Transgenic Endosomes Biology Axonal Transport Amyloid beta-Protein Precursor Mice 03 medical and health sciences 0302 clinical medicine Alzheimer Disease Lysosome Genetics medicine Amyloid precursor protein Animals Humans Axon Molecular Biology Genetics (clinical) Neurons Articles General Medicine Axons Cell biology Retromer complex 030104 developmental biology medicine.anatomical_structure nervous system Proteolysis Axoplasmic transport biology.protein Amyloid Precursor Protein Secretases Lysosomes 030217 neurology & neurosurgery trans-Golgi Network |
| Zdroj: | Human Molecular Genetics. 26:4352-4366 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddx321 |
| Popis: | Lysosomal proteolysis is essential for the quality control of intracellular components and the maintenance of cellular homeostasis. Lysosomal alterations have been implicated as one of the main cellular defects contributing to the onset and progression of Alzheimer's disease (AD). However, the mechanism underlying lysosomal deficits in AD remains poorly understood. Here, we reveal that lysosomal deficits are attributed to retromer dysfunction induced by altered retromer trafficking in the axon of AD-related mutant human amyloid precursor protein (hAPP) transgenic (Tg) mouse neurons. We demonstrate that retrograde transport of retromer is impaired, leading to its significant reduction in the soma and abnormal retention within late endosomes in distal axons of mutant hAPP neurons. Therefore, retromer-mediated endosome-to-Golgi retrieval of cation-independent mannose-6-phosphate receptors (CI-MPR) in the soma is disrupted in mutant hAPP neurons, causing defects in lysosome biogenesis. Such defects result in protease deficiency in lysosomes and impaired lysosomal proteolysis, as evidenced by aberrant accumulation of sequestered substrates within lysosomes. Intriguingly, enhancement of retrograde transport in mutant hAPP neurons facilitates the trafficking of axonal retromer toward the soma and thus enhances protease transport to lysosomes, thereby restoring lysosomal proteolytic activity. Taken together, our study provides new insights into the regulation of retromer trafficking through retrograde axonal transport to fulfil its function in promoting lysosome biogenesis in the soma, suggesting a potential approach for rescuing lysosomal proteolysis deficits in AD. |
| Databáze: | OpenAIRE |
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