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
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.
Amyotrophic lateral sclerosis (Lou Gehrig’s)
Digestive system of the cell
Bud from Golgi
Rich in lytic enzymes
Acid hydrolases active at pH 5 (inside lysosome)
Sites where digestion occurs
Heterophagosomes Digestion of materials exogenous to the cell
Digestion of cells and cell components
Post-digestive 2° lysosomes
“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
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.
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”
Gangliosidosis resulting from deficiency of hexosaminidase
Affects brain and eyes; fatal during childhood
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
Neurological deterioration; premature death
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
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
E.g., ankyrin, spectrin, dystrophin
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
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
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
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 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