Golgi apparatus, lysosomes, lysosomal storage diseases, cytoskeleton, intermediate filaments, microtubules, anti-tumor therapy, histogenesis, epithelium

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Biomedical Science
BMS 460
D.Rao Veeramachaneni

4 September Golgi Apparatus Terminal protein processing, packing, and transport Golgi is an organelle, not an extension of SER As with all cellular organelles, the Golgi has to grow and divide and has to be inherited. The Golgi decides whether a given protein will leave the cell or be delivered to the cell surface or another destination. Golgi sorts and modifies cell products such as hormones, growth factors and digestive enzymes. E.g., addition of mannose-6-phosphate (M6P) tags to lysosomal enzyme precursors In inclusion-cell (I-cell or Mucolipidosis II) disease, Golgi is unable to tag proteins with M6P because of a defective phosphotransferase. This results in secretion of lysosomal enzyme precursors from the cell instead of targeting them to lysosomes, resulting in impaired lysosomal function leading to cellular inclusions and death in childhood. Golgi apparatus is fragmented in neurodegenerative diseases and cell death. Neuronal Golgi fragmentation is an early and probably irreversible lesion in neurodegeneration, caused by a variety of mechanisms. Alzheimer’s disease Amyotrophic lateral sclerosis (Lou Gehrig’s) Creutzfeldt-Jacob disease Lysosomes Digestive system of the cell 1° lysosomes Bud from Golgi Rich in lytic enzymes Acid hydrolases active at pH 5 (inside lysosome) 2° lysosomes Sites where digestion occurs Heterophagosomes Digestion of materials exogenous to the cell Autophagosomes Digestion of cells and cell components Post-digestive 2° lysosomes Residual bodies Lipofuscin granules “Wear and tear” pigment Indicates age of cell Lysosomal Storage Diseases Inherited deficiency of one or more lysosomal enzymes causes accumulation of materials that normally would be degraded ___osis – condition ___oses – conditions Several genetic disorders in which the enzymes involved in intermediary metabolism are defective resulting in Glycogenoses Mucopolysaccharidoses Lipidoses Sphingolipidoses Sphingolipids are named for the sphingosine backbone that is the counterpart of glycerol in phospholipids. They are derived from a common precursor, ceramide, which is produced from sphingosine. Sphingolipids serve a structural and recognition role in membranes and are synthesized in the cells where they are needed. Sphingolipids are normally digested by lysosomes and a deficiency of any of these enzymes blocks the removal of any remaining sugars leading to accumulation of undigested substrates. Clinical manifestations may involve multiple tissues and organs. Pompe’s disease Glycogenosis resulting from deficiency of alpha 1,4-glucosidase Enlarged liver and heart; fatal in children but not in adults Hunter and Hurler syndromes Mucopolysaccharidoses Involve skeletal system and CNS; “gargoylism” Tay-Sachs disease Gangliosidosis resulting from deficiency of hexosaminidase Affects brain and eyes; fatal during childhood Gaucher disease Deficiency of glucocerebrosidase Enlargement of spleen and anemia; not fatal Niemann-Pick disease types A and B Deficiency of sphingomyelinase Mental retardation, hepatosplenomegaly Niemann-Pick disease type C Unlike types A and B, NPC is not a primary sphingomyelinase deficiency Cholesterol lipidosis resulting from defective intracellular transport of unesterified cholesterol Neurological deterioration; premature death Cytoskeleton Three major components – microtubules, microfilaments, and intermediate filaments – exhibit characteristic structures and have distinct functions Microtubules are found in the cytoplasm of all cells radiating from the centrosome, or microtubule organizing center (MTOC), which regulates their growth Move chromosomes Microfilaments support and maintain cell shape (cortical actin network), adhere to the extracellular matrix and to other cells Intermediary filaments strengthen the cellular cytoskeleton The 3 principal types of protein filaments are formed from different proteins Intermediate filament proteins are cell-type-specific Microfilaments – actin, myosin Intermediate filaments – epithelial: keratins; mesenchymal: vimentin; muscle: desmin; glia: glial fibrillary acidic protein; nerve: neurofilaments Microtubules – tubulin A large number of accessory proteins are essential for cytoskeletal function E.g., many functions of microfilaments depend on their association with various actin-binding proteins Anchoring proteins E.g., ankyrin, spectrin, dystrophin Cross-linking products E.g., actinin, filamin Different accessory proteins in different tissues Immunostaining for cytoskeletal elements Because intermediate filament proteins are cell-type-specific, these are useful markers for identifying Cell types and Transformations in pathologic specimens The origin of some tumors can be determined, e.g., tumors of muscle origin contain desmin and lack kertains; tumors of epithelial origin contain keratins and lack vimentin, those in transition contain both Defective ankyrin and/or spectrin in RBC cause spherocytosis and elliptocysosis Autosomal dominant disorders Membrane protein defect results in the loss of RBC membrane and spherocyte formation Increased permeability of spherocytes to sodium Due to membrane defect and dysfunctional Na /K ATPase pump With mutations of ankyrin and/or spectyrin that affect the integrity of the membrane cytoskeleton, the normal biconcave erythrocyte loses membrane fragments. To accommodate the loss of surface area, the cell adopts a spherical shape. Such spherocytic cells are less deformable than normal and are therefore trapped in the splenic cords, where they are phagocytosed by macrophages. Intermediate Filaments: Examples of Abnormal Assembly Expression of mutant keratin genes results in the abnormal assembly of intermediate filaments, which weakens the mechanical strength of cells and causes inherited skin diseases Epidermis Topmost layer: stratum corneum, contains keratin 9 Stratum granulosum/stratum spinosum contain keratin 1 and 10 Stratum basale contains keratins 5 and 14 Epidermolytic plantopalmar keratoderma (EPPK) Mutation of keratin 9 This disorder is restricted to the epidermis of palms and soles. Epidermolytic hyperkeratosis (EH) Mutation of keratins 1 and 10 Excessive keratinization causes a breakdown of the epidermis. Epidermolysis bullosa simplex (EBS) Mutation of keratins 5 and 14 Blisters develop soon after birth at sites subject to pressure or rubbing. Microtubules Microtubules are organized into several specialized structures The mitotic spindle and centrioles, which are found in most cells Cilia, flagella and basal bodies, which have a more limited distribution Microtubule-associated proteins (MAPs) Assembly MAPs function primarily to stabilize microtubules, cross-linking them to each other and to other structures. Motor MAPs (motor proteins) use energ
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