Basic mechanisms of neurodegeneration: a critical update

Introduction Protein aggregation 'Toxic oligomer' hypothesis Protein (mis)folding Proteostasis and molecular chaperones Protein misfolding and endoplasmic reticulum stress Unfolded protein response Interaction of proteins The ubiquitin proteasome system Autophagy and neurodegeneration UPS in neurodegenerative disorders Aggresomes Oxidative injury Metals and oxidative stress Oxidative stress in Alzheimer disease Oxidative stress in Parkinson disease Oxidative stress in other neurodegenerative disorders Impaired bioenergetics and mitochondrial dysfunction Mitochondrial dysfunction in Alzheimer and Parkinson disease Fragmentation of neuronal Golgi apparatus Disruption of cellular/axonal transport Axonal transport in tauopathies Axonal transport in synucleinopathies Axonal transport in other neurodegenerative diseases Dysfunction of neurotrophins 'Neuroinflammatory' processes The final pathway: multifaceted neuronal death Cell death cascades in major NDDs Acknowledgements Neurodegenerative diseases are characterized by progressive dysfunction of specific populations of neurons, determining clinical presentation. Neuronal loss is associated with extra and intracellular accumulation of misfolded proteins, the hallmarks of many neurodegenerative proteinopathies. Major basic processes include abnormal protein dynamics due to deficiency of the ubiquitin-proteosome-autophagy system, oxidative stress and free radical formation, mitochondrial dysfunction, impaired bioenergetics, dysfunction of neurotrophins, 'neuroinflammatory' processes and (secondary) disruptions of neuronal Golgi apparatus and axonal transport. These interrelated mechanisms lead to programmed cell death is a long run over many years. Neurodegenerative disorders are classified according to known genetic mechanisms or to major components of protein deposits, but recent studies showed both overlap and intraindividual diversities between different phenotypes. Synergistic mechanisms between pathological proteins suggest common pathogenic mechanisms. Animal models and other studies have provided insight into the basic neurodegeneration and cell death programs, offering new ways for future prevention/treatment strategies.