Stephen Haggarty, United States of America
Massachusetts General Hospital NeurologyAuthor Of 1 Presentation
DRP1 AND TAU INCREASE MITOCHONDRIAL FISSION IN AMYOTROPHIC LATERAL SCLEROSIS
Abstract
Aims
Although mitochondrial dysfunction has been widely described in amyotrophic lateral sclerosis (ALS), the mechanisms underlying these alterations remain to be elucidated. Here, we sought to verify whether the accumulation of the microtubule binding protein tau, and dynamin-related protein 1 (DRP1), the GTPase catalyzing mitochondrial fission, cause mitochondrial fragmentation in ALS.
Methods
Synaptoneurosomes (SNs) were prepared from ALS and control post-mortem motor cortex (mCTX). Western blots, and immunohistochemistry were used to assess tau, and DRP1 levels. Mitochondrial number and axonal degeneration were assessed by electron microscopy. DRP1 and tau interactions were studied by co-immunoprecipitation (co-IP). Mitochondrial morphology was assessed in SH-SY5Y cells following treatment with tau, ALS or control SNs in the absence or presence of DRP1 silencing (siDRP1) and a selective tau degrader (QC-01-175).
Results
Our results indicate that there was a decrease in the number of mitochondria in ALS together with an increase in DRP1. Furthermore, tau fibrils were observed in the white matter from ALS mCTX together with an increase in axonal degeneration. Additionally, hyperphosphorylated tau mis-localized to the synapses, and was shown to interact with DRP1 in ALS. Lastly, treatment of SHSY5Y cells with ALS SNs, enriched in both pTau and DRP1, significantly increased mitochondrial fission by reducing mitochondrial length and volume. Importantly, knocking down DRP1 or reducing tau levels significantly mitigated alterations in mitochondrial length and volume induced by ALS SNs.
Conclusions
Together, our findings suggest that increases in DRP1 and pTau cause mitochondrial fragmentation in ALS and importantly targeting this molecular pathway mitigates these alterations.