Neurodegenerative Disease

Based on Australian lectures

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  • Neuro-Degeneration
    • Protein Based
      • Amyloid
        • Alzheimers
          • characterised by extracellular A(b) amyloid plaques and intracellular tau tangles (interfibrillary tangles)
            • A(b) plaques accumulate adjacent to neural axons therefore interrupting axonal and synaptic interactions, so synaptic degeneration occurs first, then neuronal degeneration
              • microglia activated in response to neuronal and synaptic degeneration (and recognise a(b) plaque as foreign sbstance), produce toxic cytokines (IL1(b) and TNF), etc, to kill neurons, therefore, increasing inflammation and neuronal death
              • oligomeric form is the toxic form
          • A(b) produced from beta and gamma cut, compared to alpha and gamma cut
            • A(b) protein consists of 40-42 amino acids (the more AA, the more toxic because it can aggregate faster)
          • mutations in presinilin 1 and 2 modulate gamma cleavage of APP
            • mutations in APP may affect aloha ability to cleave protein
          • mutations in APP may affect aloha ability to cleave protein
          • interfibrillary tau tangles produced from hyper-phosphorylation of tau so that that dissociate from microtubules causing collapse of cytoskeletal structure
          • Pathogenic factors
            • Oxidative Stess = production of free radicals from mitochondria to allow Cu association with A(b) plaques and aggregation
              • leads to lipid peroxidation, protein oxidation and DNA oxidation, and therefore -neuronal toxicity and death
                • Neural inflammation
                  • microglia activated in response to neuronal and synaptic degeneration (and recognise a(b) plaque as foreign sbstance), produce toxic cytokines (IL1(b) and TNF), etc, to kill neurons, therefore, increasing inflammation and neuronal death
                  • may also be caused be A(b) intraneuronal accumulation inhibitting cell trafficking, synaptic toxicity, aberrant cell signalling from A(b) interaction with receptors, ER stress and excitotoxicity from loss of astrocyte function due to A(b) or lack of glucose
                  • less energy production due to loss ofglucose or A(b)impacting mitochondrial function, therefore ox stress and loss of synaptic ability
                    • Oxidative Stess = production of free radicals from mitochondria to allow Cu association with A(b) plaques and aggregation
                      • leads to lipid peroxidation, protein oxidation and DNA oxidation, and therefore -neuronal toxicity and death
                        • Neural inflammation
                          • may also be caused be A(b) intraneuronal accumulation inhibitting cell trafficking, synaptic toxicity, aberrant cell signalling from A(b) interaction with receptors, ER stress and excitotoxicity from loss of astrocyte function due to A(b) or lack of glucose
                          • less energy production due to loss ofglucose or A(b)impacting mitochondrial function, therefore ox stress and loss of synaptic ability
                        • also NMDA glutamate receptor interacts with amyloid protein, changing its function leading to increase in Ca (production of ROS),  andchanges in synaptic function
                • also NMDA glutamate receptor interacts with amyloid protein, changing its function leading to increase in Ca (production of ROS),  andchanges in synaptic function
              • Metal Imbalance = Cu and Zn necessary for plaques to aggregate
            • Treatment
              • biomarkers
                • tau
                • A(b)
              • imaging
                • PET imaging by looking for  gamma rays of injected PET ligand with radioisotope
                • use amyloid-binding ligands
                  • Tht doesn't pas BBB therefore must modify into C-PiB or F-PiB (which allows us to take our time)
              • because AD is associated with synaptic loss, it is therefore believed there is loss of cholinergic function, so need to use acetylcholinerase inhibiotrs to prevent breakdown of acteylcholine
              • best to treat underlying pathology - tau/amyloid
                • tramiprosate binds to A(B) maintains it in non-fibrillous state so that it can't aggregate, but failed in phase 3
                • cliogquinol chelates Zn and Cu to prevent aggregation
                • gamma secretase inhibitors bad because gamma secreatase necessary for other processes
              • active anti A(b) vaccine, where Ab can cross BBB
                • but no significant effect, and some had encephalitis
                  • inappropriate T activation?
                • A(b) plaques were cleared but neurodegeneration continued
              • passive antibodies, only solanezumab worked
          • Parkinson's
            • Braak Stages: 1) vagus of lower brain, 2) pons of brain stem, 3) SN mid brain, 4-6) temporal mesocortex, temporal neocortex and neocortex
            • characterised by Lewy bodies of a-synuclein amyloid aggregation intracellularly, affecting dopaminergic neurons
              • Oligomeric forms cleared by ubiquitin+proteosome pathway, while fibrils cleared through phagolytic pathway - however, aging and ox stress prevent autophagy clearance
              • spreads and propagates between cells through secretory vesicles, endosomes and MVB exosomes
                • results in neuronal inflammation, charcterised by production and release of Il1(b) and TNF
                • can be specifically neurotoxic
                  • results in neuronal inflammation, charcterised by production and release of Il1(b) and TNF
            • A53T and A30P mutations in a-SN allow aggregation at hydrophobic region
              • Genetics
                • Multiple Sclerosis
                  • by measuring SNP in populations with MS and populations with MS, discovered high difference in 4-5 MHC HLA complex genes - so there is some sort of autoimmunity and loss of tolerance
                    • Genome Wide Association Studies
                      • measures freqency of SNP differences between two groups of individuals
                      • allows gene mapping for common diseases across entire genome
                      • significance of SNP difference implies that the SNP is near the causal gene
                      • uses linkage disequilibrium (correlation of SNP in alleles on the same chromosomes) to understand genotype/phenotype associations
                    • also found causal connections Chr20 (CD40) and Chr12 (CYP27B1)
                      • CD40 = costimulatory molecule, so it affects activation of CD4+ T and B cells
                      • vitamin D acitvating gene that adds hydroxy group and allows vitamin D to modulate immune response (also regulates Ca metabolism)
                        • sunlight/vitamin D hypothesis (Tas has higher risk compared to QLD, so lack of vitamin D means inability to modulate immune response?
                      • find the most correlated SNPs (the ones that are closest to causal gene) and determine candidate region - by knowing candidate region we can figure out which genes are in there and deduce the causal gene
                    • has genetic and environmental risks
                      • sunlight/vitamin D hypothesis (Tas has higher risk compared to QLD, so lack of vitamin D means inability to modulate immune response?
                  • involves demyelination of neuronal axons by immune system
                    • glial cells and activated peripheral T cells play large role
                  • Treatments
                    • disease-modifying drugs
                    • since most successful drugs act on gene/protein targets, casual gene validation is necessary for successful drug development
                  • has genetic and environmental risks
                  • Genome Wide Association Studies
                    • measures freqency of SNP differences between two groups of individuals
                    • allows gene mapping for common diseases across entire genome
                    • significance of SNP difference implies that the SNP is near the causal gene
                    • uses linkage disequilibrium (correlation of SNP in alleles on the same chromosomes) to understand genotype/phenotype associations
                  • SNP polymorphism of met vs val indicates susceptibility to type of disease
                  • gene dosage: higher number of gene copies leads to more rapid disease period and shorter incubation period
              • mutations in PINK and parkin prevent inhibtion of mitochondrial fragmentation caused by a-SN interaction with mitochondria
                • Genetics
                  • Multiple Sclerosis
                    • by measuring SNP in populations with MS and populations with MS, discovered high difference in 4-5 MHC HLA complex genes - so there is some sort of autoimmunity and loss of tolerance
                      • also found causal connections Chr20 (CD40) and Chr12 (CYP27B1)
                        • CD40 = costimulatory molecule, so it affects activation of CD4+ T and B cells
                        • vitamin D acitvating gene that adds hydroxy group and allows vitamin D to modulate immune response (also regulates Ca metabolism)
                          • find the most correlated SNPs (the ones that are closest to causal gene) and determine candidate region - by knowing candidate region we can figure out which genes are in there and deduce the causal gene
                      • involves demyelination of neuronal axons by immune system
                        • glial cells and activated peripheral T cells play large role
                      • Treatments
                        • disease-modifying drugs
                        • since most successful drugs act on gene/protein targets, casual gene validation is necessary for successful drug development
                    • SNP polymorphism of met vs val indicates susceptibility to type of disease
                    • gene dosage: higher number of gene copies leads to more rapid disease period and shorter incubation period
                  • Oligomeric forms cleared by ubiquitin+proteosome pathway, while fibrils cleared through phagolytic pathway - however, aging and ox stress prevent autophagy clearance
                • Al/Cu binding causes faster aggregation
                  • Metal Based
                    • Metal Imbalance = Cu and Zn necessary for plaques to aggregate
                    • Motor Neuron
                      • Cu necessary for SOD1 antioxidant function, therefore without Cu, no SOD1 and oxidative stress
                        • metal-deficient SOD1 = toxic, therefore require at least two metals for mature Holo form
                        • Level of SOD1 correlates with severity of disease, but Cu increases SOD1 because of how it improves metal state
                        • pathogenesis occurs because of lack of bioavailability probably
                      • Ceruloplasmin can't function without Cu to allow redox of Fe so that it can be released through other membrane protein, therefore ultimate Fe accumulation within cells
                      • Riluzole is only available treatment with decent effects, with range of adverse effects
                • dopamine prevents a-SN aggregation in both monomers and fibrils, by modifying protein and making it solube
                  • unknown which form is toxic form
                  • toxic form interacts with membrane to create Ca+ channels that allow influx of Ca and activation of cell death pathways
                • Treatment
                  • L-dopa - passes through BBB as precursor for dopamine
                  • MAO-B inhibitors prevent breakdown of dopamine
                  • Dopamine agonists to stimulate relaxing action of dopamine
                  • anti-cholinergic drugs to prevent uptake of acetylcholine and reduce movement
                  • PET imaging using F-AV which looks for vesicular monomer that is involved with dopamine transport anding
            • Prions
              • High transmissibility within species and across species
              • sporadic, familial or iatrogenic
              • PrPC -> PrPSc
                • PrPC is necessary for pathogenesis of disease as PrPSc must convert PrPC into pathogenic form
                • PrPSc is definitely the pathogenic cause because misfolded protein alone without introduction of PrPSc still results in neurodegeneration
                  • unknown how exactly PrPSc causes disease (possibly through aberrant signalling, cell death, neuronal inflammation, oxidative stress etc.
                  • interacts with number of cofactors such as RNA, lipids, etc
                • beta sheet structure, with glycosylation sites, with anchorage to membrane
                  • misfolding occurs dependent on charge of cofactors and heparan sulfate
                    • interacts with number of cofactors such as RNA, lipids, etc
                    • heparan sulfate charge determines its function
                    • conversion in presence of heparan/hep sulfate determines soluble vs insoluble
              • species barrier refers to the transmissibility of prions from one species into another
              • there are different strains of prions even within the same species
                • vCJD is diglycosylated compared to CJF which is monoglycosylated
                • electrophoretic ability of HY/DY hamster strains
          • Metal Based
            • Motor Neuron
              • Cu necessary for SOD1 antioxidant function, therefore without Cu, no SOD1 and oxidative stress
                • metal-deficient SOD1 = toxic, therefore require at least two metals for mature Holo form
                • Level of SOD1 correlates with severity of disease, but Cu increases SOD1 because of how it improves metal state
                • pathogenesis occurs because of lack of bioavailability probably
              • Ceruloplasmin can't function without Cu to allow redox of Fe so that it can be released through other membrane protein, therefore ultimate Fe accumulation within cells
              • Riluzole is only available treatment with decent effects, with range of adverse effects

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