Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA.

International Journal of Molecular Sciences
Fiona LimanaqiFrancesco Fornai

Abstract

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. These include proteins which are encoded by genes containing nucleotide repeat expansions. In the present review we focus on the overlapping role of autophagy and the UPS in repeat expansion proteotoxicity associated with chromosome 9 open reading frame 72 (C9ORF72) and androgen receptor (AR) genes, which are implicated in two motor neuron disorders, amyotrophic lateral sclerosis (ALS) and spinal-bulbar muscular atrophy (SBMA), respectively. At baseline, both C9ORF72 and AR 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. Besides proteotoxicity, autophagy and UPS alterations are also implicated in neuromuscular junction (NMJ) alterations, which occur early in both ALS and SBMA. 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...Continue Reading

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Citations

Sep 7, 2020·The FEBS Journal·Stephen E GirardinDamien Arnoult
Sep 10, 2020·International Journal of Molecular Sciences·Sara BachillerRocío Ruiz
May 1, 2021·International Journal of Molecular Sciences·Ellya BukharaevaAndrei Tsentsevitsky
May 18, 2021·Journal of Neural Transmission·Federica FulceriFrancesco Fornai

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Methods Mentioned

BETA
transgenic
protein-folding
ubiquitination

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