Thursday, 8 November 2018

Are you TORCing tau me? Amyloid‐β blocks the conversation between lysosomes and mitochondria

http://emboj.embopress.org/content/early/2018/11/02/embj.2018100839

Juan Carlos Polanco, Jürgen Götz


INTRODUCTION
This EMBO News&views paper is about recent progress on how amyloid‐β (Aβ) and tau exacerbate Alzheimer's disease (AD) at a subcellular level.
A link has been established between type 2 diabetes and AD: insulin dysregulation occurs in brain tissue from AD patients and mouse models for AD.

mTOR (the protein kinase mammalian target of rapamycin) is a key molecule in the insulin signalling: its hyperactivation mediates insulin resistance, which is one cause of type 2 diabetes.

AD is characterized by the aggregation of two molecules: the peptide amyloid‐β (Aβ) and the protein tau, which impair neuronal function. This accumulation has been linked to lysosomal dysfunction.

Lysosomes and mitochondria both malfunction in various human diseases. This makes sense in the light of the discovery of mitochondria–lysosome membrane contact sites. This could mean that these two organelles also cooperate in physiological conditions.


RECENT DEVELOPMENTS
In the same issue of EMBO, Norambuena et al provide evidence that oligomeric forms of Aβ (Aβos) disrupt the functional crosstalk between lysosomes and mitochondria, thereby contributing to the early stages of AD.

It was already known that mitochondrial dysfunction impairs lysosomal structure and function in a manner that depends on the levels of mitochondrial ROS.

Norambuena et al have provided evidence that that there is also an opposite information flow, with mitochondria receiving signals from lysosomes. This mechanism is dependent on mTORC1, a multiprotein signalling complex nucleated by mTOR and bound to the cytosolic side of lysosomes. This mTORC1 was shown to be activated by insulin and amino acids, leading to what the authors have called “nutrient‐induced mitochondrial activation (NiMA)”,

This lysosomal signalling was strongly inhibited by Aβos and was found to depend on the activation of mTORC1 by a mechanism that requires tau. Indeed, NiMA was not blocked by Aβos in tau knockout neurons.


This reinforces the view that tau facilitates the formation of signalling complexes affecting neuronal function. Future research could be targeted at the isolation and characterization of these putative complexes.

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