Everything points to mTOR dysfunction in ALS

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Here we review recent publications about ALS and try to connect the dots between autophagy, insulin resistance, C9orf72, FUS, proteopathies, mitophagy and defective neuromuscular junction. It seems autophagy dysregulation is central to all those aspects of ALS.

TDP-43

Over the past decade, it has become increasingly clear that the most notable neurodegenerative diseases, such as ALS, FTLD, and AD, share a common prominent pathological feature known as TAR DNA-binding protein 43 (TDP-43) proteinopathy, which is usually characterized by the presence of aberrant phosphorylation, ubiquitination, cleavage and/or nuclear depletion of TDP-43 in neurons and glial cells. The role of TDP-43 as a neurotoxicity trigger has been well documented in different in vitro and in vivo experimental models.

There is increasing evidence that autophagy is defective in neurodegenerative disorders, including motor neurons affected in amyotrophic lateral sclerosis (ALS). Restoring impaired autophagy in motor neurons may therefore represent a rational approach for ALS. In this publication the clinically approved anti-hypertensive drug rilmenidine was used to stimulate mTOR-independent autophagy in double transgenic TDP-43WTxQ331K mice to alleviate impaired autophagy.

Although rilmenidine treatment induced robust autophagy in spinal cords, this exacerbated the phenotype of TDP-43WTxQ331K mice, truncated lifespan, accelerated motor neuron loss, and pronounced nuclear TDP-43 clearance.

Importantly, rilmenidine significantly promoted mitophagy in spinal cords TDP-43WTxQ331K mice, evidenced by reduced mitochondrial markers and load in spinal motor neurons. These results suggest that autophagy induction accelerates the phenotype of this TDP-43 mouse model of ALS, most likely through excessive mitochondrial clearance in motor neurons.

C9orf72

The coordinated activities of autophagy and the ubiquitin proteasome system (UPS) are key to preventing the aggregation and toxicity of misfold-prone proteins which manifest in a number of neurodegenerative disorders.

Both C9ORF72 and androgen receptors regulate autophagy, while their aberrantly-expanded isoforms may lead to a failure in both autophagy and the UPS, further promoting protein aggregation and toxicity within motor neurons and skeletal muscles.

In fact, autophagy and the UPS intermingle with endocytic/secretory pathways to regulate axonal homeostasis and neurotransmission by interacting with key proteins which operate at the NMJ.

FUS

The mechanism by which FUS affects the translation of polyribosomes has not been established. In a recent publication, the authors show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian target of rapamycin) kinase activity. Specifically, they show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1.

Moreover, they report that FUS is necessary for efficient stalling of translation because deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin. The scientists also show that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling and that ALS-linked FUS mutants can cause a toxic gain of function in the cytoplasm by repressing the translation of mRNA at polyribosomes.

Stress granules

It was recently reported that the stress granule (SG) protein Staufen1 (STAU1) was overabundant in neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2) patient cells, animal models, and ALS-TDP-43 fibroblasts, and provided a link between SG formation and autophagy.

The authors demonstrate STAU1 overabundance and increased total and phosphorylated mammalian target of rapamycin (mTOR) in fibroblast cells from patients with ALS with mutations in TDP-43, patients with dementia with PSEN1 mutations, a patient with parkinsonism with MAPT mutation, Huntington's disease (HD) mutations, and SCA2 mutations.

Increased STAU1 levels and mTOR activity were seen in human ALS spinal cord tissues as well as in animal models. Changes in STAU1 and mTOR protein levels were post-transcriptional. Exogenous expression of STAU1 in wildtype cells was sufficient to activate mTOR and downstream targets and form SGs.

mTOR

The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.

As usual it must be underlined that mTOR is important for living beings, and simply inhibiting it is out of question. It would simply further starve motor neurons and exacerbate the disease as shown above.

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1 doi: 10.3390/ijms21114021. Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA Fiona Limanaqi 1, Carla Letizia Busceti 2, Francesca Biagioni 2, Federica Cantini 1, Paola Lenzi 1, Francesco Fornai 1 2 2 doi: 10.1016/j.nbd.2021.105359. Online ahead of print. Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice Nirma D Perera 1, Doris Tomas 1, Nayomi Wanniarachchillage 1, Brittany Cuic 1, Sophia J Luikinga 1, Valeria Rytova 1, Bradley J Turner 2 3 doi: 10.1074/jbc.RA120.013801. Epub 2020 Oct 20. FUS contributes to mTOR-dependent inhibition of translation Myriam Sévigny 1, Isabelle Bourdeau Julien 1, Janani Priya Venkatasubramani 1, Jeremy B Hui 1, Paul A Dutchak 1, Chantelle F Sephton 2 4 doi: 10.1002/ana.26069. Online ahead of print. Staufen1 in Human Neurodegeneration Sharan Paul 1, Warunee Dansithong 1, Karla P Figueroa 1, Mandi Gandelman 1, Daniel R Scoles 1, Stefan M Pulst 1

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