Abstract
Motor neuron diseases (MNDs) are fatal diseases characterized by loss of motor neurons in the brain cortex, in the bulbar region, and/or in the anterior horns of the spinal cord. While generally sporadic, inherited forms linked to mutant genes encoding altered RNA/protein products have also been described. Several different mechanisms have been found altered or dysfunctional in MNDs, like the protein quality control (PQC) system. In this review, we will discuss how the PQC system is affected in two MNDs—spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS)—and how this affects the clearance of aberrantly folded proteins, which accumulate in motor neurons, inducing dysfunctions and their death. In addition, we will discuss how the PQC system can be targeted to restore proper cell function, enhancing the survival of affected cells in MNDs.
Highlights
Motor neuron diseases (MNDs) are neurodegenerative diseases (NDs) characterized by the loss of motor neurons in the brain cortex, in the bulbar region, and/or in the anterior horns of the spinal cord; the consequence of motor neuron death is the lack of control on the skeletal muscle fibers
Components of the chaperone-assisted selective autophagy (CASA) complex may affect/take part in extracellular vesicles pathway: for example, STUB1/CHIP deficiency resulted in an increased secretion of small extracellular vesicles that are enriched in ubiquitinated and/or undegraded proteins and protein oligomers (Ferreira et al, 2019), and BAG3 is found to be involved in the exosome secretion of mutant Huntingtin upon proteasome blockade (Diaz-Hidalgo et al, 2016)
We showed that while the wtAR with a 23Q stretch can be cleared via the proteasome even in presence of androgens (Rusmini et al, 2007), the mutant ARpolyQ may impair the ubiquitin proteasome system (UPS) function; by expressing the ARpolyQ in basal condition, we noted an accumulation of the proteasome activity reporter GFP-CL1 (GFPu) as an indication that the elongated polyQ is poorly processed by the UPS and interferes with the activity of this degradative pathway
Summary
Riccardo Cristofani 1, Valeria Crippa 1, Maria Elena Cicardi 1,2, Barbara Tedesco 1, Veronica Ferrari 1, Marta Chierichetti 1, Elena Casarotto 1, Margherita Piccolella 1, Elio Messi 1, Mariarita Galbiati 1, Paola Rusmini 1 and Angelo Poletti 1,3*. Quality Control System in Motor Neuron Diseases. Motor neuron diseases (MNDs) are fatal diseases characterized by loss of motor neurons in the brain cortex, in the bulbar region, and/or in the anterior horns of the spinal cord. While generally sporadic, inherited forms linked to mutant genes encoding altered RNA/protein products have been described. Several different mechanisms have been found altered or dysfunctional in MNDs, like the protein quality control (PQC) system. We will discuss how the PQC system is affected in two MNDs—spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS)—and how this affects the clearance of aberrantly folded proteins, which accumulate in motor neurons, inducing dysfunctions and their death. We will discuss how the PQC system can be targeted to restore proper cell function, enhancing the survival of affected cells in MNDs
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