Cell Biology of Neurodegenerative Diseases
1. General introduction Common features of the neurodegenerative disorders: i/ intra- or extracellular accumulation of pathologic protein isoforms; ii/ regional and selective neuron death; iii/ reactive astrogliosis; iiii/ familiar and sporadic forms. Clinico-pahological characterization of the main groups of neurodegenerative diseases (Alzheimer’s, Parkinson’s and Huntington disease, Amyotrophic Lateral Sclerosis).
2. Prion diseases Prion disease: a new entity. Its significance in biomedical and basic research. Classification of prion diseases: human and animal forms. Brief characterization of scrapie, bovine spongiform encephalopathy (BSE), kuru and Creutzfeldt-Jakob disease. Infectivity, as a unique phenomenon. Unusual features of the “pathogen”: extraordinary resistance, lack of normal immune response. Slow virus – virino – prion.
3. The prion hypothesis The infectious protein: information transfer without nucleic acid; the heterodimer concept by Prusiner. Discovery, structure, localization and functions of cellular prion protein (PrPC); comparison with its pathologic conformational isoform (PrPSc). The possible subcellular sites and mechanism of the PrPC - PrPSc interaction, and the potential role of protein-X in the conformational transformation. Recent experimental proofs of prion hypothesis.
4. Cell pathology of prion infection Ultrastructural and immunocytochemical studies on the molecular cell biological mechanisms of prion pathogenesis in neuronal cell models, and in prion-infected wild type, knock-out and transgenic animal models.
5. Molecular cell biology of Alzheimer’s disease I. The structure, synthesis, transport, membrane topology and functions of the amyloid precursor protein (APP). The normal and pathologic (amyloidogenic) processing of APP. The structure, function and regulation of alpha---ines, and their roles in the APP-plaques. The amyloid-cascade hypothesis.
6. Molecular cell biology of Alzheimer’s disease II. The structure and functions of tau, an important neuronal microtubule-associated protein. Phosphorylation-dephosphorylation, hyperphosphorylation: regulation and misregulation of the tau-microtubule dynamic interactions. “Intracellular movement disorder”: disorganization of microtubule network, inhibition of intracellular protein and vesicle transport, axon degeneration, as the consequences of the intracellular aggregation of tau. “Tauists” and “Baptists” finally shake hands (?) Genetic ground of the familiar Alzheimer cases.
7. Molecular cell pathology of Parkinson’s disease Strict regional histopathology and remarkably selective cell death. Types and structures of synuclein proteins. Subcellular localization of alpha-synuclein, and its role in the transport and docking of synaptic vesicles. Molecular interactions of alpha-synuclein. Oxidative stress - alpha-synuclein aggregation – neurodegeneration. Familiar Parkinson cases = ubiquitin-proteasome system disorders (?)
8. Animal models of neurodegenerative diseases Studies on molecular biology and genetic of neurodegenerative diseases in invertebrate organisms (C. elegans, Drosophila). Animal models of prion transmissibility. PrPC knock-out animals, break-trough in prion research. Transgenic models for Alzheimer’s, Parkinson’s and Huntington diseases.
9. The plasma membrane and the cytoskeleton in the neurodegeneration The specific structure of neuronal cell membrane: lipid rafts and ion-channels. beta-caused changes of membrane fluidity and ion-permeability. The role of lipid rafts in the cluster formation and interaction of GPI-anchored prion proteins; inhibition of PrPSc formation by cholesterol depletion. Lipid homeostasis – ApoE – pathogenesis of Alzheimer’s disease. Disorganization of the actin, intermedier filament and microtubule network in the early stages of neurodegeneration.
10. The role of mitochondrial system and the ER in the neurodegeneration Intracellular calcium homeostasis and the role of the mitochondria and the endoplasmic reticulum. Subnecrotic Ca-ion toxicity, saturation of intracellular Ca-puffer capacity. The role of mitochondria in the modulation of oxidative stress. Mitochondrial and ER membrane damages, release of cell death signals, intense neuronal cell death.
11. Endosome/lysosome system and the neurodegeneration Subcompartments and functions of the endosome/lysosome system (ELS). Formation of multivesicular bodies and exosomes, and their roles in the protein sorting and in the intracellular fate of segregated proteins. The role of ELS in the biogenesis, accumulation and “purification” of proteins with pathologic conformation. The ELS and the pathogenesis of prion and Alzheimer’s disease. The ELS, as a therapeutic target
12. The role of the ubiquitin-proteasome system and the heat-shock proteins in the neurodegeneration and neuroprotection The components of the ubiquitin-proteasome system (UPS), and the mechanism of ubiquitinilation. The recognition, reparation, isolation and elimination of damaged proteins require the collaboration of UPS and Hsp-s. Function disorders of UPS and the molecular processes of neurodegeneration in Alzheimer’s, Parkinson’s and prion diseases.
13. Autophagy in the neurodegeneration and neuroprotection The mechanism and physiological significance of autophagy in health and disease. “Friend or foe?”: enhanced autophagic activity in Alzheimer’s, Parkinson’s and Huntington diseases. Complement and/or cooperative role of the UPS and the autophagy in neuroprotection. Selective segregation and degradation of damaged mitochondria by autophagy in degenerating neurons.
14. Neurodegeneration and ageing (Summary) Neurodegeneration = accelerated ageing (?) Common cell- and molecular biological features of neurodegeneration and neuronal cell death in the progress of ageing and different neurodegenerative diseases.
David B. Teplow: Molecular Biology of Neurodegenerative Diseases (in: Progress in molecular biology and translational science), Academic Press, 2012, ISBN 9780123858832
Thomas M. Durcan, Heather L. Montie: The Cell and Molecular Biology of Neurodegenerative diseases, Frontiers E-books, 2014, ISBN 9782889191932