Molecular Basis of Aging: Loss of Proteostasis & Neurodegeneration Lecture Notes PDF

Molecular basis of Aging: Loss of Proteostasis & Neurodegeneration 2X: Fundamental Topics in Biology Aging & Disease (lecture 3) Prof. Iain Johnstone November 2023 lides by Iain Johnstone and Dr Christina Elliot Loss of proteostasis...

Molecular basis of Aging: Loss of Proteostasis & Neurodegeneration 2X: Fundamental Topics in Biology Aging & Disease (lecture 3) Prof. Iain Johnstone November 2023 lides by Iain Johnstone and Dr Christina Elliot Loss of proteostasis is a key hallmark of aging Protein aggregation is a key feature in neurodegenerative disease Dementia is not just a part of getting old. It is a disease with biological mechanisms Aims of this lecture Understand the key components that regulate proteostasis Appreciate the role of protein aggregation in aging and late- onset neurodegenerative disease Understand genetics of the most prevalent age-related neurodegenerative disease- Alzheimer’s Disease (AD) Describe the molecular basis for neurodegeneration in early onset familial AD Proteostasis in aging Wild type Young adult worms maintain a balanced proteome by effectively clearing misfolded proteins. Ageing is associated with proteome imbalance Inefficient clearance of misfolded proteins and mis-regulated transcription Loss of chaperones e.g. sHSP (small heat shock protein). Increase in the number of toxic misfolded protein oligomers Insoluble inclusions- large aggregates of misfolded oligomers. Age-1 mutants Just like DNA, proteins can also be damaged Aging Increased damage Failure of removal mechanisms A vicious cycle Ubiquitin forms. Removal Repair Dysfunction and disease A balancing Protein production Protein act removal Protein production Protein aggregation Loss of chaperones Protein clearance Proteosome Autophagy  Protein aggregation and neurodegeneration Alzheimer’s Disease Parkinson’s Disease Protein aggregation is a common feature in late-onset neurodegenerative diseases Why? Human brain – most sophisticated biological instrument in nature Energy usage: 10-15 Watts >1016 complex operations/second (10 petaflops) K Supercomputer (RIKEN, Japan) 88,128 processors 8.162 petaflops 9.89MW Google Brain Project: AI development informed by biology Metabolism in the brain is key Neurons are the brains cellular processors There are approximately 37 trillion cells in the human body 100 billion neurons 100 trillion connections (“synapses”) – 1000 synapses per neuron 3.2 million km nerve fiber network (80 times around the globe) Neurons are responsible for storage and retrieval of biological data Neurons terminally differentiated and non-proliferative Cells Proliferate At Different Rates Mitotic cells: Quiescent/ post-mitotic: Fixed post mitotic cells: continuously low or no division but no division even under a dividing can be stimulated to stimulus. divide. Skin cells Liver cells Neurons Lifespan: ~3 Lifespan: ~200-300 Lifespan: life course weeks days Cell cycle: - Cell cycle: 12-24 Cell cycle: 1-2 years hour Defined by Cells age at different rates too: telomere lengths vary function With great power, comes great susceptibility The long-lived nature of neurons is essential to their function but also its their biggest vulnerability A 100-year-old person will have 100-year-old neurons (and some as young as 80 years old). Neurons must endure a lifetime of biological “insults” Neurons must repair themselves- not replaced Non-dividing: misfolded protein builds up Neurons do continuously adjust, or “remodel,” their synaptic connections depending on how much stimulation they receive from other neurons. Alzheimer’s Disease Dementia is NOT part of normal aging it is a disease of aging. Therefore there are biological mechanisms behind it. Understanding the relationship between aging, loss of proteostasis and neuron loss is essential to treating the disease The first clue came from GENETICS The genetic landscape of AD 2 types of AD Familial (early-onset 65) Genetic risks General population SNPs with small effect sizes GWAS ApoE4 genotype is the biggest genetic risk factor for LOAD New hypotheses form from genetic data e.g. Neuroinflammation Amyloid-β Precursor Protein (APP) Aβ peptide is a small fragment of the APP protein APP protein has a structure like some cell surface receptors involved in a variety of cell signalling pathways Transmembrane protein Function is not completely known Implicated in signalling of Neuronal Stem Cell development. Implicated in intracellular signalling systems promoting growth of axonal and dendritic processes and in synaptic maintenance and remodelling Synaptic Plasticity*. Implicated in regulating lipid homeostasis possibly regulating expression of some enzymes involved in synthesis of specific lipids.  Familial Alzheimer’s Disease Alzheimer’s Disease Familial Alzheimer’s Disease is unimodal progeroid disease Early onset often 50% Down’s syndrome develop dementia (due to AD) Some don’t- other factors Age of onset ~50-60 (early) AD has two major pathological hallmarks Extracellular amyloid plaques Alzheimer’s Disease (Aβ) (pink) Intracellular neurofibrillary tangles (tau) (black) Mutations in the tau gene (MAPT) linked to other forms of dementia (frontotemporal dementia), but not familial AD.  Microtubule associated protein Tau (MAPT) Nucleus in cell body Axon (very long) Axon terminus Proteins, organelles axon transported from cell body to Cell body synapse Microtubule dynamics plays essential role in active transport of axonal proteins, vesicles and organelles throughout the axon Essential for synaptogenesis. Tau stabilises microtubules. In AD, microtubules dissociate, release tau. Tau aggregated in NFTs (neurofibrillary tangles) Does Aβ amyloid or Tau fibrils cause AD? Both are associated with AD, but is either or both the cause? Specific mutations in PSEN and APP exist the cause FAD with 100% penetrance (all carriers get AD). These increase the amount of Aβ 42 produced. Rare mutations in APP exist that protect against AD and these decrease beta-secretase cleavage which increases alpha-secretase cleavages. This significantly reduces all Aβ. The existence of both causative and protective APP alleles strongly suggests Aβ is primary cause. Tau certainly can’t cause AD on its own because some alleles of APP prevent AD. That versions of APP can prevent AD proves that other versions (non- protective ones) are needed to produce AD.  New therapeutic strategies for AD? * * So far it had not been very successful. Current efforts focused on clearance.