TDP-43 is a causative factor of amyotrophic lateral sclerosis (ALS). Cytoplasmic TDP-43 aggregates in neurons are a hallmark pathology of ALS. Under various stress conditions, TDP-43 localizes sequentially to two cytoplasmic protein aggregates: stress granules (SGs) first, and then aggresomes. Accumulating evidence suggests that delayed clearance of TDP-43-positive SGs is associated with pathological TDP-43 aggregates in ALS. We found that USP10 promotes the clearance of TDP-43-positive SGs in cells treated with proteasome inhibitor, thereby promoting the formation of TDP-43-positive aggresomes, and the depletion of USP10 increases the amount of insoluble TDP-35, a cleaved product of TDP-43, in the cytoplasm. TDP-35 interacted with USP10 in an RNA-binding dependent manner; however, impaired RNA-binding of TDP-35 reduced the localization in SGs and aggresomes and induced USP10-negative TDP-35 aggregates. Immunohistochemistry showed that most of the cytoplasmic TDP-43/TDP-35-aggregates in the neurons of ALS patients were USP10-negative. Our findings suggest that USP10 inhibits aberrant aggregation of TDP-43/TDP-35 in the cytoplasm of neuronal cells by promoting the clearance of TDP-43/TDP-35-positive SGs and facilitating the formation of TDP-43/TDP-35-positive aggresomes.
Adiponectin is a multifunctional adipocytokine produced predominantly by adipocytes, with potent antiinflammatory, insulin-sensitizing, and cytoprotective properties. Autophagy is a lysosome-dependent self-degradative process that mediates the degradation of damaged organelles, invading pathogens and protein aggregates, thus maintaining cellular homeostasis. Adiponectin performs different biological functions by regulating autophagy. This review attempts to elucidate the biological responses and potential mechanisms underlying adiponectin-induced autophagy, with an aim to guide the identification of new therapeutic targets of related diseases. Keywords: Adiponectin, adiponectin receptors, autophagy
Neurodegenerative diseases are accompanied by oxidative stress and mitochondrial dysfunction, leading to a progressive loss of neuronal cells, formation of protein aggregates, and a decrease in cognitive or motor functions. Mitochondrial dysfunction occurs at the early stage of neurodegenerative diseases. Protein aggregates containing oxidatively damaged biomolecules and other misfolded proteins and neuroinflammation have been identified in animal models and patients with neurodegenerative diseases. A variety of neurodegenerative diseases commonly exhibits decreased activity of antioxidant enzymes, lower amounts of antioxidants, and altered cellular signalling. Although several molecules have been approved clinically, there is no known cure for neurodegenerative diseases, though some drugs are focused on improving mitochondrial function. Mitochondrial dysfunction is caused by oxidative damage and impaired cellular signalling, including that of peroxisome proliferator-activated receptor gamma coactivator 1α. Mitochondrial function can also be modulated by mitochondrial biogenesis and the mitochondrial fusion/fission cycle. Mitochondrial biogenesis is regulated mainly by sirtuin 1, NAD+, AMP-activated protein kinase, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ. Altered mitochondrial dynamics, such as increased fission proteins and decreased fusion products, are shown in neurodegenerative diseases. Due to the restrictions of a target-based approach, a phenotype-based approach has been performed to find novel proteins or pathways. Alternatively, plasma membrane redox enzymes improve mitochondrial function without the further production of reactive oxygen species. In addition, inducers of antioxidant response elements can be useful to induce a series of detoxifying enzymes. Thus, redox homeostasis and metabolic regulation can be important therapeutic targets for delaying the progression of neurodegenerative diseases.
Many neurodegenerative diseases are characterized by abnormal protein aggregates, including the two most common neurodegenerative diseases Alzheimer’s disease (AD) and Parkinson’s disease (PD). In the global search to prevent and treat diseases, most research has been focused on the early stages of the diseases, including how these pathogenic protein aggregates are initially formed. We argue, however, that an equally important aspect of disease etiology is the characteristic spread of protein aggregates throughout the nervous system, a key process in disease progression. Growing evidence suggests that both alterations in lipid metabolism and dysregulation of extracellular vesicles (EVs) accelerate the spread of protein aggregation and progression of neurodegeneration, both in neurons and potentially in surrounding glia. We will review how these two pathways are intertwined and accelerate the progression of AD and PD. Understanding how lipid metabolism, EV biogenesis, and EV uptake regulate the spread of pathogenic protein aggregation could reveal novel therapeutic targets to slow or halt neurodegenerative disease progression.
Protein aggregates of cofilin and actin have been found in neurons under oxygen–glucose deprivation. However, the regulatory mechanism behind the expression of Cfl1 during oxygen–glucose deprivation remains unclear. Here, we found that heterogeneous nuclear ribonucleoproteins (hnRNP) Q and hnRNP A1 regulate the translation of Cfl1 mRNA, and formation of cofilin–actin aggregates. The interaction between hnRNP A1 and Cfl1 mRNA was interrupted by hnRNP Q under normal conditions, while the changes in the expression and localization of hnRNP Q and hnRNP A1 increased such interaction, as did the translation of Cfl1 mRNA under oxygen–glucose deprived conditions. These findings reveal a new translational regulatory mechanism of Cfl1 mRNA in hippocampal neurons under oxygen–glucose deprivation.
Amyloids are filamentous protein aggregates that are associated with a number of incurable diseases, termed amyloidoses. Amyloids can also manifest as infectious or heritable particles, known as prions. While just one prion is known in humans and animals, more than ten prion amyloids have been discovered in fungi. The propagation of fungal prion amyloids requires the chaperone Hsp104, though in excess it can eliminate some prions. Even though Hsp104 acts to disassemble prion fibrils, at normal levels it fragments them into multiple smaller pieces, which ensures prion propagation and accelerates prion conversion. Animals lack Hsp104, but disaggregation is performed by the same complement of chaperones that assist Hsp104 in yeast—Hsp40, Hsp70, and Hsp110. Exogenous Hsp104 can efficiently cooperate with these chaperones in animals and promotes disaggregation, especially of large amyloid aggregates, which indicates its potential as a treatment for amyloid diseases. However, despite the significant effects, Hsp104 and its potentiated variants may be insufficient to fully dissolve amyloid. In this review, we consider chaperone mechanisms acting to disassemble heritable protein aggregates in yeast and animals, and their potential use in the therapy of human amyloid diseases.
Autophagy is a physiological process that facilitates the recycling of intracellular cytosolic components as a response to diverse stressful conditions. By increasing the turnover of damaged structures and clearance of long-lived and larger protein aggregates, the induction of autophagy increases tolerance to abiotic stress in a range of organisms. However, the contribution of this process to heat-tolerance of insect models remains poorly studied to date. Here, we report that rapamycin exposure in Drosophila melanogaster induces autophagy in flies, which in turn correlates with an increase in heat tolerance and quicker recovery from heat-coma. This confirms the potentially important role of the autophagic process in heat tolerance mechanisms in this organism, opening the path to further characterization of its relationship to thermal acclimation and molecular level processes related to stress.
AbstractSelective autophagy is an evolutionarily conserved mechanism that removes excess protein aggregates and damaged intracellular components. Most eukaryotic cells, including neurons, rely on proficient mitophagy responses to fine-tune the mitochondrial number and preserve energy metabolism. In some circumstances (such as the presence of pathogenic protein oligopolymers and protein mutations), dysfunctional mitophagy leads to nerve degeneration, with age-dependent intracellular accumulation of protein aggregates and dysfunctional organelles, leading to neurodegenerative disease. However, when pathogenic protein oligopolymers, protein mutations, stress, or injury are present, mitophagy prevents the accumulation of damaged mitochondria. Accordingly, mitophagy mediates neuroprotective effects in some forms of neurodegenerative disease (e.g., Alzheimer's disease, Parkinson’s disease, Huntington's disease, and Amyotrophic lateral sclerosis) and acute brain damage (e.g., stroke, hypoxic–ischemic brain injury, epilepsy, and traumatic brain injury). The complex interplay between mitophagy and neurological disorders suggests that targeting mitophagy might be applicable for the treatment of neurodegenerative diseases and acute brain injury. However, due to the complexity of the mitophagy mechanism, mitophagy can be both harmful and beneficial, and future efforts should focus on maximizing its benefits. Here, we discuss the impact of mitophagy on neurological disorders, emphasizing the contrast between the positive and negative effects of mitophagy.
Ordered protein aggregates, amyloid fibrils, are a marker of many serious diseases, such as Alzheimer’s, Parkinson’s, prion diseases, etc. At present, special attention is paid to the study of external influences that can affect the structure and stability of mature amyloid fibrils, which may be in demand in the development of approaches to the therapy of amyloidosis, as well as in the creation of new high-strength materials on the basis of these protein aggregates. An external factor, the influence of which on fibrils was studied in this work, was temperature denaturation. It was shown that heating lysozyme amyloid fibrils to 60 °C does not lead to their degradation, but leads only to a reversible increase in the intramolecular mobility of amyloid-forming proteins, but does not change their morphology. At the same time, boiling of lysozyme amyloids leads to their irreversible degradation, which occurs at least 5 days after exposure: fibrils that form larger clusters change their secondary structure, and fibrils with a lesser degree of clustering are divided into separate fibers. Obtained data about the factors that change the stability and structure of amyloids can be applied in biotechnology for creating new high-strength nanomaterials on their basis.