bromochloroacetic-acid and Neurodegenerative-Diseases

Cytoskeletal research in recent years has revolutionized cell biology and biomedicine. The cytoskeleton spans the cytoplasm and interconnects the cell nucleus with the extracellular matrix, thereby forming a structural link between molecules involved in cell communication on the one hand, and gene expression on the other. Since the cytoskeleton is involved in virtually all cellular processes, abnormalities in this essential cellular component frequently result in disease. In this introduction, the basic structure of the cytoskeleton is briefly outlined. Furthermore, the disease processes in which the cytoskeleton plays a decisive role, and which are reviewed in detail in the papers in this issue, are briefly introduced. The advances in our understanding of the cytoskeleton and its function in disease will lead to new diagnostic and therapeutic applications in the foreseeable future.

Topics: Actins; Cell Nucleus; Cytoskeletal Proteins; Cytoskeleton; Hematologic Diseases; Humans; Intestinal Diseases; Keratins; Liver Diseases; Lymphatic Diseases; Muscular Diseases; Neurodegenerative Diseases; Skin Diseases

Topics: Amyotrophic Lateral Sclerosis; Animals; Biomarkers; Case-Control Studies; Female; Humans; Keratins; Mercury; Neurodegenerative Diseases

Exposure of cells to stress, particularly oxidative stress, leads to misfolding of proteins and, if they are not refolded or degraded, to cytoplasmic protein aggregates. Protein aggregates are characteristic features of a variety of chronic toxic and degenerative diseases, such as Mallory bodies (MBs) in hepatocytes in alcoholic and non-alcoholic steatohepatitis, neurofibrillary tangles in neurons in Alzheimer's, and Lewy bodies in Parkinson's disease. Using 2D gel electrophoresis and mass spectrometry, we identified p62 as a novel MB component. p62 and cytokeratins (CKs) are major MB constituents; HSP 70, HSP 25, and ubiquitinated CKs are also present. These proteins characterize MBs as a prototype of disease-associated cytoplasmic inclusions generated by stress-induced protein misfolding. As revealed by transfection of tissue culture cells overexpressed p62 did not induce aggregation of regular CK filaments but selectively bound to misfolded and ubiquitinated CKs. The general role of p62 in the cellular response to misfolded proteins was substantiated by detection of p62 in other cytoplasmic inclusions, such as neurofibrillary tangles, Lewy bodies, Rosenthal fibers, intracytoplasmic hyaline bodies in hepatocellular carcinoma, and alpha1-antitrypsin aggregates. The presence of p62 along with other stress proteins and ubiquitin in cytoplasmic inclusions indicates deposition as aggregates as a third line of defense against misfolded proteins in addition to refolding and degradation.

Topics: Adaptor Proteins, Signal Transducing; alpha 1-Antitrypsin Deficiency; Animals; Astrocytoma; Central Nervous System Neoplasms; CHO Cells; Cricetinae; Heat-Shock Proteins; Humans; Inclusion Bodies; Keratins; Liver Diseases; Mice; Neurodegenerative Diseases; Protein Binding; Protein Folding; Proteins; Sequestosome-1 Protein; Stress, Physiological; Ubiquitin