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Truncated Tau Induces Mitochondrial Transport Failure Through the Impairment of TRAK2 Protein and Bioenergetics Decline in Neuronal Cells
dc.contributor.author | Quintanilla R.A. | |
dc.contributor.author | Tapia-Monsalves C. | |
dc.contributor.author | Vergara E.H. | |
dc.contributor.author | Pérez M.J. | |
dc.contributor.author | Aranguiz A. | |
dc.date.accessioned | 2020-09-02T22:26:28Z | |
dc.date.available | 2020-09-02T22:26:28Z | |
dc.date.issued | 2020 | |
dc.identifier | 10.3389/fncel.2020.00175 | |
dc.identifier.citation | 14, , - | |
dc.identifier.issn | 16625102 | |
dc.identifier.uri | https://hdl.handle.net/20.500.12728/5930 | |
dc.description | Mitochondria are highly specialized organelles essential for the synapse, and their impairment contributes to the neurodegeneration in Alzheimer’s disease (AD). Previously, we studied the role of caspase-3–cleaved tau in mitochondrial dysfunction in AD. In neurons, the presence of this AD-relevant tau form induced mitochondrial fragmentation with a concomitant reduction in the expression of Opa1, a mitochondrial fission regulator. More importantly, we showed that caspase-cleaved tau affects mitochondrial transport, decreasing the number of moving mitochondria in the neuronal processes without affecting their velocity rate. However, the molecular mechanisms involved in these events are unknown. We studied the possible role of motor proteins (kinesin 1 and dynein) and mitochondrial protein adaptors (RhoT1/T2, syntaphilin, and TRAK2) in the mitochondrial transport failure induced by caspase-cleaved tau. We expressed green fluorescent protein (GFP), GFP-full-length, and GPF-caspase-3–cleaved tau proteins in rat hippocampal neurons and immortalized cortical neurons (CN 1.4) and analyzed the expression and localization of these proteins involved in mitochondrial transport regulation. We observed that hippocampal neurons expressing caspase-cleaved tau showed a significant accumulation of a mitochondrial population in the soma. These changes were accompanied by evident mitochondrial bioenergetic deficits, including depolarization, oxidative stress, and a significant reduction in ATP production. More critically, caspase-cleaved tau significantly decreased the expression of TRAK2 in immortalized and primary hippocampal neurons without affecting RhoT1/T2 and syntaphilin levels. Also, when we analyzed the expression of motor proteins—Kinesin 1 (KIF5) and Dynein—we did not detect changes in their expression, localization, and binding to the mitochondria. Interestingly, the expression of truncated tau significantly increases the association of TRAK2 with mitochondria compared with neuronal cells expressing full-length tau. Altogether these results indicate that caspase-cleaved tau may affect mitochondrial transport through the increase of TRAK2–mitochondria binding and reduction of ATP production available for the process of movement of these organelles. These observations are novel and represent a set of exciting findings whereby tau pathology could affect mitochondrial distribution in neurons, an event that may contribute to synaptic failure observed in AD. © Copyright © 2020 Quintanilla, Tapia-Monsalves, Vergara, Pérez and Aranguiz. | |
dc.language.iso | en | |
dc.publisher | Frontiers Media S.A. | |
dc.subject | kinesin | |
dc.subject | mitochondria | |
dc.subject | tau | |
dc.subject | TRAK2/Milton | |
dc.subject | transport | |
dc.subject | truncated tau | |
dc.subject | adenosine triphosphatase | |
dc.subject | caspase | |
dc.subject | caspase 3 | |
dc.subject | dynein adenosine triphosphatase | |
dc.subject | green fluorescent protein | |
dc.subject | hypochlorite sodium | |
dc.subject | kinesin 1 | |
dc.subject | kinesin 5A | |
dc.subject | lipofectamine | |
dc.subject | membrane protein | |
dc.subject | mitochondrial protein | |
dc.subject | outer membrane protein | |
dc.subject | Rho factor | |
dc.subject | RhoT1 protein | |
dc.subject | RhoT2 protein | |
dc.subject | superoxide | |
dc.subject | syntaphilin | |
dc.subject | tau protein | |
dc.subject | TRAK2 protein | |
dc.subject | unclassified drug | |
dc.subject | animal cell | |
dc.subject | animal experiment | |
dc.subject | Article | |
dc.subject | bioenergy | |
dc.subject | cell structure | |
dc.subject | cell transport | |
dc.subject | controlled study | |
dc.subject | depolarization | |
dc.subject | epifluorescence microscopy | |
dc.subject | genetic transfection | |
dc.subject | hippocampal neuronal culture | |
dc.subject | immunofluorescence | |
dc.subject | mitochondrial membrane potential | |
dc.subject | mitochondrial permeability | |
dc.subject | mitochondrion | |
dc.subject | mRNA expression level | |
dc.subject | nerve cell | |
dc.subject | nonhuman | |
dc.subject | oxidative stress | |
dc.subject | protein expression | |
dc.subject | protein localization | |
dc.subject | protein phosphorylation | |
dc.subject | protein processing | |
dc.subject | rat | |
dc.subject | real time polymerase chain reaction | |
dc.subject | retrovirus infection | |
dc.subject | Western blotting | |
dc.title | Truncated Tau Induces Mitochondrial Transport Failure Through the Impairment of TRAK2 Protein and Bioenergetics Decline in Neuronal Cells | |
dc.type | Article |