Shared Molecular Mechanisms in Alzheimer's Disease and Amyotrophic Lateral Sclerosis: Neurofilament-Dependent Transport of sAPP, FUS, TDP-43 and SOD1, with Endoplasmic Reticulum-Like Tubules
| العنوان: | Shared Molecular Mechanisms in Alzheimer's Disease and Amyotrophic Lateral Sclerosis: Neurofilament-Dependent Transport of sAPP, FUS, TDP-43 and SOD1, with Endoplasmic Reticulum-Like Tubules |
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| المؤلفون: | Virgil Muresan, Zoia Muresan |
| المصدر: | Neurodegenerative Diseases. 16:55-61 |
| بيانات النشر: | S. Karger AG, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | 0301 basic medicine, Neurofilament, Neurite, Nogo Proteins, Growth Cones, SOD1, Intermediate Filaments, Peripherins, Biology, Endoplasmic Reticulum, Article, Cell Line, Amyloid beta-Protein Precursor, 03 medical and health sciences, Superoxide Dismutase-1, 0302 clinical medicine, Alzheimer Disease, medicine, Humans, Amyotrophic lateral sclerosis, Neurons, Superoxide Dismutase, Endoplasmic reticulum, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, Biological Transport, Peripherin, medicine.disease, DNA-Binding Proteins, 030104 developmental biology, Neurology, RNA-Binding Protein FUS, Neurology (clinical), Neuroscience, Myelin Proteins, 030217 neurology & neurosurgery, Brain Stem, Reticulon 4 |
| الوصف: | Background: Amyotrophic lateral sclerosis (ALS), a debilitating neurodegenerative disorder of the motor neurons, leads to the disorganization of the neurofilament (NF) cytoskeleton and - ultimately - the deterioration of the neuromuscular junction. Some familial cases of ALS are caused by mutated FUS, TDP-43 or SOD1; it is thought that the mutated proteins inflict pathology either by gain or loss of function. The proper function of the neuromuscular junction requires sAPP, a soluble proteolytic fragment of the amyloid-β precursor protein (APP) - a transmembrane protein implicated in the pathology of Alzheimer's disease (AD). Whether sAPP, FUS, TDP-43 and SOD1 are mechanistically linked in a common pathway deregulated in both AD and ALS is not known. Summary: We show that sAPP, TDP-43, FUS and SOD1 are transported to neurite terminals by a mechanism that involves endoplasmic reticulum (ER)-like tubules and requires peripherin NFs. The transport of these proteins, and the translocation of the ER protein reticulon 4 (Rtn4) into neurites was studied in CAD cells, a brainstem-derived neuronal cell line highly relevant to AD and ALS. We show that a significant fraction of sAPP is generated in the soma and accumulates in a juxtanuclear ER subdomain. In neurites, sAPP localizes to Rtn4-positive ER-like tubules that extend from the soma into the growth cone and colocalizes with peripherin NFs. Knocking down peripherin disrupts the NF network and diminishes the accumulation of sAPP, TDP-43, FUS, SOD1 and Rtn4 at terminals. Key Messages: We propose that the impediment of a common, ER-mediated mechanism of transport of sAPP, TDP-43, FUS and SOD1, caused by a disrupted NF network, could be part of the mechanisms leading to AD and ALS. |
| تدمد: | 1660-2862 1660-2854 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5c6ed943c847193c75c640044f0a3bb0Test https://doi.org/10.1159/000439256Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5c6ed943c847193c75c640044f0a3bb0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16602862 16602854 |
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