Editorial: Protein Misfolding and Proteostasis Impairment in Aging and Neurodegeneration: From Spreading Studies to Therapeutic Approaches

• Published in: Frontiers in aging neuroscience Vol. 13; p. 830779
• Main Authors: Duran-Aniotz, Claudia, Moreno-Gonzalez, Ines, Medinas, Danilo B., Morales, Rodrigo
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 09.02.2022; Frontiers Media S.A
• Subjects: Aging; Aging Neuroscience; Alzheimer's disease; Amyotrophic lateral sclerosis; Animal models; Cell culture; DNA-binding protein; FUS protein; Kinases; mRNA; Neurodegeneration; Older people; Protein biosynthesis; Protein folding; protein misfolding; Protein seeding; proteostasis; Puromycin; Ribosomes; Sarcoma; Superoxide dismutase; Transgenic mice; neurodegeneration; aging; proteostasis; Alzheimer's disease; protein misfolding
• ISSN: 1663-4365; 1663-4365
• DOI: 10.3389/fnagi.2021.830779

The authors cover literature involving biochemical and seeding properties of major ALS-linked proteins including superoxide dismutase 1 (SOD1), transactive response DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) in different systems including invertebrate and mammalian models. According to the evidence discussed, redox modifications such as S-nitrosylation and ALS-linked mutations in PDIs impair their redox activity, resulting in protein misfolding and disulfide-dependent aggregation. Employing cell culture and transgenic mouse models, the authors show that cytoplasmic TDP-43 impairs the proteostasis network by inhibiting translation, which was monitored by puromycin labeling, in addition to preparation of mRNA-ribosome complexes from brain tissue. According to the authors, multiple mechanisms may be associated to suppression of protein synthesis by TDP-43 that deserve further investigation, including disruption of mRNA recruitment by ribosomes, sequestration of ribosome components into protein inclusions, aberrant formation of stress granules, ER stress and activation of the unfolded protein response, among others.