Soluble 4R0N Tau Abrogates Endocytic Vesicular Dynamics.

Tharun Selvam Mahendran,Ravi Manjithaya,S N Suresh,Lakshmi Garimella

doi:10.3389/fnagi.2020.537712

Tharun Selvam Mahendran, Ravi Manjithaya + Show 2 more

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https://doi.org/10.3389/fnagi.2020.537712

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Abstract

Aggregated tau is a hallmark neuropathological feature in numerous neurodegenerative disorders. Previous studies aiming to validate aggregated tau pathology as a pathogenic driver of neurodegeneration in correlation to characteristic behavioral phenotypes have had shortcomings. Although studies on soluble tau pathology have effectively addressed these shortcomings, the role of soluble tau in the molecular pathogenesis of neurodegeneration is not yet unequivocally established. In sporadic Alzheimer’s disease (AD), the relevance of soluble tau pathology in endolysosomal dysfunction and autophagic stress, some of the earliest disease manifestations, is unclear. In this study, we report that soluble 4R0N tau overexpression affects the expression levels of certain markers associated with the endolysosomal system and autophagy. Moreover, through live-cell imaging, we found that the vesicular dynamics of early endosomes were affected with respect to spatiotemporal parameters and vesicle maturation. Additionally, we observed the localization of amyloid precursor protein (APP) along the endocytic pathway and found that upon overexpression of soluble 4R0N tau, APP was preferentially localized to the endocytic compartments implicated in the amyloidogenic pathway. Overall, our observations indicate that soluble 4R0N tau abrogates the dynamics of the endolysosomal system, autophagy, and affects the trafficking of APP. Since the amyloidogenic processing of APP occurs during its progression through the endocytic pathway, our results suggest that the generation of amyloid-β (Aβ) might also be modulated.

Highlights

Tau is an intrinsically disordered proteinaceous cytoskeletal element known to associate with microtubules and bundle actin filaments (Weingarten et al, 1975; He et al, 2009; Morris et al, 2011), and it is highly expressed in the human central nervous system as six major isoforms via alternative splicing (Mandelkow and Mandelkow, 2012)
We found that the expression levels of RAB5 (p < 0.0001), RAB7 (p < 0.05), and LAMP1 (p < 0.0001) were significantly upregulated in HeLa cells transiently transfected with 4R0N tau compared to HeLa cells transiently transfected with the vector control
We found that soluble 4R0N tau overexpression leads to decreased beclin-1 expression, which is in agreement with Alzheimer’s disease (AD)-related clinical studies (Rohn et al, 2011; Orr and Oddo, 2013)

Summary

Introduction

Tau is an intrinsically disordered proteinaceous cytoskeletal element known to associate with microtubules and bundle actin filaments (Weingarten et al, 1975; He et al, 2009; Morris et al, 2011), and it is highly expressed in the human central nervous system as six major isoforms via alternative splicing (Mandelkow and Mandelkow, 2012). Gain-of-function toxicity of tau has been implicated in the pathogenesis of AD, which is predominantly characterized by the presence of pathological protein aggregates such as tau aggregates and amyloid-β (Aβ) containing senile plaques (Mitchell et al, 2002; Maeda et al, 2006; Johnson et al, 2016; Schöll et al, 2016). This toxicity was presumably attributed to aggregated tau formed by the nucleation events involving soluble tau, mediated by liquid–liquid phase separation (Ambadipudi et al, 2017; Wegmann et al, 2018). There is a lack of evidence to unequivocally establish which aggregated state(s) of tau has a role in the cascade of events leading to neurodegeneration

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