Recent advances in our understanding of neurodegeneration.
Neurodegenerative diseases are featured by progressive dysfunction and death of cells in selected areas in the nervous system, determining clinical presentation. Neuronal loss is associated with conformational changes in proteins that result in extra- and intra-cellular accumulation of misfolded proteins, representing the hallmarks of many neurodegenerative disorders, summarized as proteinopathies. Intermediate forms such as oligomers and protofibrils are thought to have cytotoxic effects to neurons. Major basic processes, caused by genetic, environmental, and endogenous factors, in addition to abnormal protein dynamics with defective degradation due to deficiency of the ubiquitin-proteosomal-autophagy system, include oxidative stress and free radical formation, impaired bioenergetics and mitochondrial dysfunction, disruption of neuronal Golgi apparatus and transport, molecular chaperones, neurotrophins and "neuroinflammatory" processes. These mechanisms are interrelated in vicious circles finally leading to programmed cell death. A common feature of these conditions is a long run until sufficient protein accumulates, followed by a cascade of symptoms over many years with increasing disability leading to death. This provides a wide therapeutic window, especially in groups at risk identified early and preclinical diagnosis becomes feasible. Neurodegenerative disorders are classified according to known genetic mechanisms or to the major components of protein deposits. Although this has been a productive paradigm for the development of diagnostic consensus criteria, recent molecular biologic and genetic approaches have revealed that there are both overlap and intraindividual diversities between different phenotypes, related to synergistic mechanisms between major pathologic proteins (beta-amyloid, tau, alpha-synuclein, TDP-43), suggesting common pathogenic mechanisms. The nature, time course, and molecular causes of cell degeneration and demise, and the role of various pathogenic factors are a matter of considerable debate, but recent studies have provided insight into the basic processes in neurodegeneration and the roles of cell death programs common to this complex group of disorders, offering new ways for future prevention and treatment strategies.
Jellinger
Kurt A
KA
Institute of Clinical Neurobiology, Vienna, Austria. kurt.jellinger@univie.ac.at
D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000145:classification / Q000150:complications / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D025801:Ubiquitin / Q000378:metabolism
D005609:Free Radicals; D009419:Nerve Tissue Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
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