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Truncated Tau Induces Mitochondrial Transport Failure Through the Impairment of TRAK2 Protein and Bioenergetics Decline in Neuronal Cells

dc.contributor.authorQuintanilla R.A.
dc.contributor.authorTapia-Monsalves C.
dc.contributor.authorVergara E.H.
dc.contributor.authorPérez M.J.
dc.contributor.authorAranguiz A.
dc.date.accessioned2020-09-02T22:26:28Z
dc.date.available2020-09-02T22:26:28Z
dc.date.issued2020
dc.identifier10.3389/fncel.2020.00175
dc.identifier.citation14, , -
dc.identifier.issn16625102
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5930
dc.descriptionMitochondria 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.isoen
dc.publisherFrontiers Media S.A.
dc.subjectkinesin
dc.subjectmitochondria
dc.subjecttau
dc.subjectTRAK2/Milton
dc.subjecttransport
dc.subjecttruncated tau
dc.subjectadenosine triphosphatase
dc.subjectcaspase
dc.subjectcaspase 3
dc.subjectdynein adenosine triphosphatase
dc.subjectgreen fluorescent protein
dc.subjecthypochlorite sodium
dc.subjectkinesin 1
dc.subjectkinesin 5A
dc.subjectlipofectamine
dc.subjectmembrane protein
dc.subjectmitochondrial protein
dc.subjectouter membrane protein
dc.subjectRho factor
dc.subjectRhoT1 protein
dc.subjectRhoT2 protein
dc.subjectsuperoxide
dc.subjectsyntaphilin
dc.subjecttau protein
dc.subjectTRAK2 protein
dc.subjectunclassified drug
dc.subjectanimal cell
dc.subjectanimal experiment
dc.subjectArticle
dc.subjectbioenergy
dc.subjectcell structure
dc.subjectcell transport
dc.subjectcontrolled study
dc.subjectdepolarization
dc.subjectepifluorescence microscopy
dc.subjectgenetic transfection
dc.subjecthippocampal neuronal culture
dc.subjectimmunofluorescence
dc.subjectmitochondrial membrane potential
dc.subjectmitochondrial permeability
dc.subjectmitochondrion
dc.subjectmRNA expression level
dc.subjectnerve cell
dc.subjectnonhuman
dc.subjectoxidative stress
dc.subjectprotein expression
dc.subjectprotein localization
dc.subjectprotein phosphorylation
dc.subjectprotein processing
dc.subjectrat
dc.subjectreal time polymerase chain reaction
dc.subjectretrovirus infection
dc.subjectWestern blotting
dc.titleTruncated Tau Induces Mitochondrial Transport Failure Through the Impairment of TRAK2 Protein and Bioenergetics Decline in Neuronal Cells
dc.typeArticle


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