Abstract
Cellular stress caused by protein misfolding, aggregation and redox imbalance is typical of neurodegenerative disorders such as Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Activation of quality control systems, including endoplasmic reticulum (ER)-mediated degradation, and reactive oxygen species (ROS) production are initially aimed at restoring homeostasis and preserving cell viability. However, persistent damage to macromolecules causes chronic cellular stress which triggers more extreme responses such as the unfolded protein response (UPR) and non-reversible oxidation of cellular components, eventually leading to inflammation and apoptosis. Cell fate depends on the intensity and duration of stress responses converging on the activation of transcription factors involved in the expression of antioxidant, autophagic and lysosome-related genes, such as erythroid-derived 2-related factor 2 (Nrf2) and transcription factor EB respectively. In addition, downstream signaling pathways controlling metabolism, cell survival and inflammatory processes, like mitogen activated protein kinase and nuclear factor-kB, have a key impact on the overall outcome. Molecular chaperones and ER stress modulators play a critical role in protein folding, in the attenuation of UPR and preservation of mitochondrial and lysosomal activity. Therefore, the use of chaperone molecules is an attractive field of investigation for the development of novel therapeutic strategies and disease-modifying drugs in the context of neurodegenerative diseases such as PD and ALS.
Highlights
Cellular stress is a mechanism of criticalphysiological significance and is generally accompanied by stress-induced responses
Cellular stress caused by protein misfolding, aggregation and redox imbalance is typical of neurodegenerative disorders such as Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS)
Activation of quality control systems, including endoplasmic reticulum (ER)-mediated degradation, and reactive oxygen species (ROS) production are initially aimed at restoring homeostasis and preserving cell viability
Summary
Cellular stress is a mechanism of critical (patho)physiological significance and is generally accompanied by stress-induced responses. SALS and FALS are clinically very similar and study of the hereditary form of the disease has provided important insights into the molecular understanding of the key pathomechanisms of the sporadic form To this regard, the first contribution toward an understanding of ALS pathogenesis has come from the discovery of mutations in the gene encoding the Cu/Zn superoxide dismutase protein or AIMS Molecular Science. It is noteworthy to mention that FALS is caused by mutations in genes directly involved in protein clearance and quality control pathways These include vesicle-associated membrane protein-associated protein B (VAPB) [20]; charged multivesicular body protein 2B or chromatin modifying protein 2B (CHMP2B) [21]; ubiquilin-2 (UBQLN2) [22]; vasolin-containing protein (VCP) [23]; optineurin (OPTN) [24]; p62/sequestosome (SQSTM1) [25,26,27]
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