Molecular Medicine NATS 3034 Lecture 7 PDF

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AccessibleBiedermeier

Uploaded by AccessibleBiedermeier

Western Sydney University

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molecular medicine genetics of brain disorders disease pathways molecular biology

Summary

This document is a lecture on molecular medicine, specifically focusing on disorders of the brain and genetics of brain disorders. It also discusses precision medicine and the power of population databases. The summary of the document covers the main topics that were addressed in the lecture, and the document itself doesn't seem to contain any exam questions.

Full Transcript

Molecular Medicine NATS 3034 Lecture 7 Split into 5 different presentations 1 – Disorders of the Brain 2 – Genetics of Brain Disorders 3 – Power of Population Databases 4 – Molecular alterations driving disease 5 – Precision medicine – teaching old drugs new tricks ...

Molecular Medicine NATS 3034 Lecture 7 Split into 5 different presentations 1 – Disorders of the Brain 2 – Genetics of Brain Disorders 3 – Power of Population Databases 4 – Molecular alterations driving disease 5 – Precision medicine – teaching old drugs new tricks Molecular Medicine NATS 3034 Lecture 7 Split into 5 different presentations 1 – Disorders of the Brain 2 – Genetics of Brain Disorders 3 – Power of Population Databases 4 – Molecular alterations driving disease 5 – Precision medicine – teaching old drugs new tricks A Basic Model of Genetics in Disease Where genetic variants lead to severe disabling disorders Selective pressure means there in infancy, the variant is not inherited and only arise is usually an inverse spontaneously. relationship between how common a genetic variant is, Ultra-rare and how severe the disease is High disease risk at a young age. Effect Size Rare variants that confer risks Common variants confer minor risks Allele Frequency Monogenic and Polygenic Disorders Monogenic disorders are conceptually simpler than Ultra-rare High disease risk polygenic disorders. Most neurological disorders are a Effect Size Rare variants that combination of monogenic and polygenic disorders. confer risks Common variants confer minor risks Allele Frequency Genetic Contributors to Stroke Malik et al, 2018 Nat Genetics To find genes that increase the risk of stroke, some 520 000 people were studied to identify genes. Many of these genes also associated with high blood pressure. Genetic Contributors to Stroke Fabry disease (GLA variants) Monogenic causes of stroke is a disorder where galactose lead to very different disorders. is not broken down in Generally, patients have lysozymes. Early stroke multiple comorbidities that onset is one of many have a defined syndrome. symptoms Genetic Contribution to Dementia How to make sense of so many different risk factors? Over 1.1 million individuals genotyped and 75 different gene loci identified. That’s a lot of genes that confer risk! Grouping the genes into function reveals disease pathways Once we know the genes involved, we need to know the Genes involved in the molecular pathways underlying the disease. metabolism of APP are associated with early onset and severe disorders. Other pathways, such as cholesterol metabolism, have a lesser risk, but affect more people! The common pathway of early-onset Alzheimer’s Ideally, if we know what causes neurodegeneration in an The APP gene combines with individual, then we can diagnose and treat the individual PSEN2 and PSEN2 to form the γ- before the disease strikes. Not happening now. secretase complex. This breaks down into Aβ42 protein that forms the plaques that are a hallmark of Alzheimer’s. Epilepsy is genetically and clinically heterogeneic Hundreds of genes have now been associated with genetic epilepsy, mainly in the last 15 years. Early-onset epilepsies have been a high priority for whole genome sequencing. Epilepsy is often a disorder of electicity Your brain can be thought of as a machine running on The gene families most often electrical impulses. When the firing of different cells gets associated with epileptic dysregulated, then seizures often result. disorders are ion channels and ion transporters. Multiple causes, multiple disorders. Inhibition and Excitation Chloride and potassium channels are major inhibitory ion Net negative current into a cell channels, calcium and potassium channels are major is inhibitory. excitatory channels. Net positive current into cell is excitatory. When enough positive current enters the cell it sets off an action potential. Overlap of pharmacology and genetics Ion channels are important drug targets. They are accessible at the membrane and act rapidly at their target. Many genetic variants are also at ion channels. But the drugs Could be in lecture 4 don’t work at these variants!

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