Atrophie bulbo-spinale liée à l’X : une maladie rare mais un diagnostic différentiel fréquent de la sclérose latérale amyotrophique

Pradat, Pierre-François

doi:10.1016/j.lpm.2014.03.005

Cited by 1 publication

(1 citation statement)

References 25 publications

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“…Here we focus on chromosome 9 open reading frame 72 (C9ORF72) and androgen receptor (AR) genes which are similarly affected by repeat expansions, leading to two different kinds of motor neuron disorders, namely ALS and SBMA, respectively [11][12][13][14]. Despite differing in disease frequency and clinical course, ALS and SBMA possess key overlapping features that are associated with dysfunctions of cell-clearing systems, namely protein aggregation due to expanded C9ORF72 or AR within both motor neurons and skeletal muscles, as well as early neuromuscular junction (NMJ) and axonal alterations [10,[15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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

Limanaqi

Busceti

Biagioni

et al. 2020

IJMS

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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 NMJ, such as agrin, acetylcholine receptors (AChRs), and adrenergic beta2 receptors (B2-ARs). Thus, alterations of autophagy and the UPS configure as a common hallmark in both ALS and SBMA disease progression. The findings here discussed may contribute to disclosing overlapping molecular mechanisms which are associated with a failure in cell-clearing systems in ALS and SBMA.

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