Cell structure & transport II (student)_20240919.pdf

Cell Structure & Transport II 19 Sep 2024 Simon Fung Why to learn Refresh what they might have learnt in BIO2036 or other courses Arouse their interest to familiarize themselves with the importance of most cell & cellular organelle functions e.g. cell vs...

Cell Structure & Transport II 19 Sep 2024 Simon Fung Why to learn Refresh what they might have learnt in BIO2036 or other courses Arouse their interest to familiarize themselves with the importance of most cell & cellular organelle functions e.g. cell vs system, organelle vs organ How this function relate to our health status and health maintenance Relationship with the dyfunction of the cytoskeleton to the relevant diseases caused Highlights Introduction to cytoskeleton Cytoskeleton – actin, microtubules, Intermediate filament Diseases with cytoskeleton defects Relationship with the dysfunction of these organelle to the relevant disease caused e.g. Cardiomyopathy Blistering skin disease  3 major filaments A. Actin filament  Thinnest, helical actin polymer  Abundant in cells e.g. muscle  Many actin-binding proteins in cell for various functions B. Microtubules  Thickest  Minute hollow tubes e.g.Help pull duplicated chromosomes C. Intermediate filament  Ropelike, intermediate size  absence in cytoplasm of plant cell with cell wall General functions to cell: Mechanical strength Control shape Drive and guide movement  Appearance  Location  Role: Maintain cell shape & structure Promote cellular movement Aid cell division during mitosis Trasport of vesicles between ER & Golgi Apparatus Molecules trafficking in cytosol etc. Albert_Eessential-cell-biology-5th-edition, Chapter 17 Actin - Structure & Role e.g. heart muscle contraction Actin in heart muscle (myofibril) structure Actin-myosin in basic unit of contractile element  Action potential > Ca2+ release> troponin binds ICF Ca2+>Cross-bridge cycling myofibrils contracts https://www.youtube.co m/watch?v=uh5ght1pkSE  Myosin moves over actin > shorten sarcomere > muscle contraction https://doctorlib.info/physiolo gy/medical-physiology- molecular/10.html Microtubule Structure Basic globular protein called tubulins - Structure & Role in In Eukaryotic cells only cell division etc. Form hollow microtubules Thread-like Role As mover or shaker of cell interior Organisation of intracellular structure and transport Cell motility Other function: Assist in the movement of vesicles from the cell bodies of neurons to the axonal tips and back to the cell bodies Formation of spindle during cell division (Mitosis) Help pull duplicated chromosomes, formation of daughter cell More…  The microtubule associated cellular transport can be accomplished both directly with self locomotion of microtubules and indirectly by presenting motor proteins named as kinesin and dynein Neurodegenerative diseases and microtubules; Microtubules essential for vesicular trafficking, endocytosis and exocytosis and axonal polarity in neuronal system. A genetic defect on regulation of superoxide dismutase (SOD) effectivity is determined as a pathogen factor for amyotrophic lateral sclerosis (ALS). Structures of Cytoskeleton and Disease Interactions, Acta Medica Alanya,2019;3(2):197-202 Various intermediate filament Most classification, composition, diverse class and tissue distribution great strength, toughest, durable withstand the mechanical stress during cells stretching About 10nm, first discovered in smooth muscle cells Location found: as network throughout the cytoplasm surrounding the nucleus (nuclear lamina) extending out to the cell periphery (desmosome) at cell-cell junction Keratin filaments - most diverse class of intermediate filament In every kind of epithelium (Vertebrate) e.g. tongue, the cornea, or the lining of the gut (with own distinctive mixture of keratin proteins) Specialized keratins also occur in hair, feathers,and claws. The ends of the keratin filaments are anchored to the desmosomes The filaments associate laterally with other cell components through the domains (head & tail) that project from their surface. Keratin filaments typically span the interiors of epithelial cells from one side of the cell to the other, and filaments in adjacent epithelial cells are indirectly connected through desmosomes These strong cables, formed by the filaments throughout the epithelial sheet, distribute the stress that occurs when the skin is stretched. Many intermediate filaments are further stabilized and reinforced by  Defects in neurofilaments can also accessory proteins e.g. plectin lead to disease. Neurofilaments are intermediate cross-link the filaments into bundles and connect them to microtubules, to filaments that are found along the actin filaments, and to adhesive axons of vertebrate neurons, where structures in desmosomes they provide strength and stability to the long axons that nerve cells use to transmit information Mutations in the gene for plectin cause The neurodegenerative disease a devastating human disease : amyotrophic lateral sclerosis (ALS, epidermolysis bullosa simplex (caused by also known as Lou Gehrig’s disease) disruption of skin keratin), is associated with an abnormal muscular dystrophy (caused by disruption of accumulation of neurofilaments in the intermediate filaments in muscle) cell bodies and axons of motor neurodegeneration (caused by disruption of neurons. neurofilaments). This gradual accumulation may precipitate the axon degeneration and muscle weakness seen in these patients. The Nuclear Envelope Is Supported by a Meshwork of Intermediate Filaments; Linker Proteins Connect Cytoskeletal Filaments and Bridge the Nuclear Envelope Defects in a particular nuclear lamin are associated with certain types of progeria—rare disorders that cause affected individuals to age prematurely. Children with progeria have wrinkled skin, lose their teeth and hair develop severe cardiovascular disease by the time they reach their teens this devastating condition is not yet clear may be that the resulting nuclear instability impaired cell division, increased cell death, a diminished capacity for tissue repair, or some combination of these.  Interaction with other proteins e.g. binding protein or molecules (Gelsolin etc.) Structure, regulation and related diseases of the actin-binding protein gelsolin | Expert Reviews in Molecular Medicine | Cambridge Core Various polymorphisms Widespread roles of cytoskeleton Cytoskeletal proteins are essential for various cellular processes in higher eukaryotes such as cell movement, stability, and cell to cell interaction. The polymerization dynamics of these three proteins are in turn regulated by several other accessory proteins depending upon the functional requirement of the cells. These polymerization dynamics of the protein are also responsible for cellular signaling processes that control the cytokine release during various immune responses against foreign particles. Any aberrant polymerization dynamics may cause diseases range from various types of cancer, polycystic ovary syndrome, neuropathological disorders, liver cirrhosis, pulmonary fibrosis, and blistering skin diseases. Responsible for various disease polymorphisms; this can be explored through the interaction dynamics of several cytoskeletal binding drugs e.g. polymerization of tubulin and actin filaments. Reminder Defective cytoskeleton and disruption of the interaction with other protein or molecules Diverse biological functions defect Various kinds of diseases Neurodegenration Cancer Angiogenesis Developmental disorder Autoimmune diseases Immunodeficiency Disease related to cytoskeleton - Cardiomyopathies Features e.g. sign & symptom The first symptom is often a heart murmur Cough and congestion, Dizziness or lightheadedness, Fainting, Fatigue, unusual tiredness, Palpitations , Shortness of breath (dyspnea) Swelling in your legs and feet (edema), Unexpected weight gain due to fluid retention. Goodman and Fuller’s Pathology, 5th Edition Dilated Cardiomyopathy (DCM) Hypertrophic Cardiomyopathy (HCM) - A Disease of Impaired Sarcomere Contraction - A Disease of Poor Sarcomere Relaxation Selected cardiomyopathy -DCM Genetic pathogenesis Monogenic causes contribute to 25–50% , TTN mutations predominate DCM mutations in other sarcomere genes, including MYH7, MYBPC3, TNNT2 Familial type - 40% of all cases over 60 genes for cytoskeleton or sacromeric proteins Mode of inheritance – Autosomal dominant (56%), recessive(16%) or X-linked (10%) Other causes Non-genetic or acquired causes e.g. viral/bacterial infection, long-term alcohol abuse, drug, end secondary to myocardial damage due to systemic or multi-organ disease Prevalence: 1:2500 (3rd most frequent cause of heart failure (HF)) whereas HCM is the most frequent (1:200 to 500) 30 – 40 age whereas HCM is more common in young (sudden cardiac death including trained athletes) Hallmark of the defect Dilated and/or poorly functioning left ventricle Systolic impairment; diastolic and/or right ventricular dysfunctions can also develop. Current Understanding of the Role of Cytoskeletal Cross-Linkers in the Onset and Development of Cardiomyopathies - PubMed (nih.gov)  Diagnosis Electrocardiogram (ECG or EKG) Test how fast or how slow the heart is beating. Patterns in the signals can help diagnose heart rhythm disease or reduced blood flow Imaging is crucial for DCM’s diagnosis, risk stratification, management, and treatment monitoring ransthoracic echocardiogram is the first-line imaging method  provides information on chamber dimensions and morphology, systolic and diastolic function, presence and severity of valve disorders, and RV dysfunction. Three-dimension (3D) TTE avoids geometric assumptions and offers superior reproducibility,if available Nuclear imaging technique can be used in DCM patients to detect myocardial perfusion defect, myocardial viability, and inducible ischemia. Holter monitor Portable device worn for a day or more to record the heart's activity during daily activities. Blood tests Check for infections, diseases e.g. DM or hemochromatosis — that may lead to dilated cardiomyopathy ? Heart failure assessment/stratification e.g. BNP Management & Treatment Goal: reduce symptoms, improve blood flow and prevent further heart damage. medications or surgery to implant a medical device that helps the heart beat or pump blood. Dilated cardiomyopathy - Diagnosis & treatment - Mayo Clinic  Medications A combination of medications may be used to treat dilated cardiomyopathy and prevent any complications. Medications are used to: Control the heart's rhythm Help the heart pump better Lower blood pressure Prevent blood clots Reduce fluid from the body Drugs that are used to treat heart failure and dilated cardiomyopathy include: Blood pressure medications. Different types of drugs may be used to lower blood pressure, improve blood flow and reduce the strain on the heart. Such medications include beta-blockers, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Sacubitril/valsartan (Entresto). This drug combines an angiotensin two receptor blocker (ARB) with another type of medicine to help the heart better pump blood to the rest of the body. It's used to treat those with chronic heart failure. Water pills (diuretics). A diuretic removes excess fluid and salt from the body. Too much fluid in the body strains the heart and can make it difficult to breathe. Digoxin (Lanoxin). This drug can strengthen heart muscle contractions. It also tends to slow the heartbeat. Digoxin may reduce heart failure symptoms and make it easier to be active. Blood-thinners (anticoagulants). These drugs help prevent blood clots. Dilated cardiomyopathy - Diagnosis & treatment - Mayo Clinic Blistering skin disease due to defective cytoskeleton -Intermediate filament (IF) Epidermolysis bullosa simplex Gene mutations in the keratin interfere with the formation of keratin filaments in the epidermis. Skin is highly vulnerable to mechanical injury can rupture easily the cells causing the skin to blister. Epidermolysis bullosa: Overview (aad.org) https://www.aad.org/public/diseases/a-z/epidermolysis-bullosa-overview Epidermolysis bullosa simplex Genetic cause Pathophysiology/Pathogenesis/Pathology - Cellular & functional defect Features e.g. sign & symptom Diagnosis – clin & lab Tx Epidermolysis Bullosa Simplex - GeneReviews® - NCBI Bookshelf (nih.gov) Epidermolysis bullosa - Mayo Clinic Orphanet (search for a rare disease): Epidermolysis bullosa simplex Other blistering skin diseases -different etiology Diseases spectrum of cytoskeleton (e.g. own defects or associated proteins) Muscle dystrophy Blistering skin diseases Neurodegeneration Immune system GIT Cancer e.g. Cholangiocacinoma Information reminder Major cell organelles, Cytoskeleton, lysosome, peroxisome pictures (Supplementary Information) https://courses.lumenlearning.com/suny-ap1/chapter/the-cytoplasm-and-cellular-organelles/ Albert_Eessential-cell-biology-5th-edition, Chapter 17