Golgi Body Diseases
Margorie Gomoran
Golgi is a highly polar organelle composed of many flat vesicles. It is often distributed between the endoplasmic reticulum and the cell membrane. It is slightly arcuate or hemispherical and has a certain polarity. The convex surface of the flat capsule is close to the nucleus or endoplasm net, called the generating surface or the immature surface, is opposite to the concave side facing the cell membrane side, called the secretory surface or the mature surface. Its main function is to process, classify and package the proteins synthesized by the endoplasmic reticulum, and then send them to specific parts of the cells or to the cells. Many studies have found that Golgi is involved not only in the secretory process of cells, but also in the post-translational modification and hydrolysis of proteins of protein glycosylation. Within neurons, the Golgi apparatus is involved in the cis, trans, and synaptic transport of many endogenous and exogenous proteins. Therefore, a certain or extensive function of the Golgi apparatus can cause abnormalities in protein and lipid transport, and even neuronal dysfunction, leading to disease.
Golgi apparatus is a highly dynamic organelle involved in the processing and classification of lipids and proteins. The maintenance of its morphology depends on the cellular transport process and the composition of many proteins. The morphology of the Golgi can change under different physiological conditions, such as cell mitosis, growth or metabolic requirements, and the Golgi changes in cells during these processes are reversible. When the drug-induced microtubule injury is caused by nocodazole or colchicine, the Golgi apparatus also reversibly disperses or fragments. In the case of pathological conditions such as impaired endoplasmic reticulum function, disruption of intracellular trafficking pathways, abnormal lipid metabolism, stress state, DNA damage, and activation of apoptotic pathways, the Golgi apparatus may also change. However, this change is generally irreversible and can even accelerate or cause cell death associated with Golgi and neurodegenerative diseases.
As aging progresses, the prevalence of neurodegenerative diseases is also rising. Golgi is increasingly being considered and studied as an important organelle. In neurons of neurodegenerative diseases, Golgi has undergone morphological changes such as cystic dilatation, rupture, reduced number, reduced volume, and reduced vesicles and adjacent vesicles associated with the rough endoplasmic reticulum, or aggregate at the periphery of the nucleus or cytoplasm. Among them, Golgi fragmentation is a typical feature of neurodegenerative diseases, and different mechanisms may be involved in different neurodegenerative diseases. Many studies have shown that the mutant copper-zinc superoxide dismutase mSOD1, β-amyloid (Aβ), alpha-synuclein, stathmin and Tau proteins are associated with Golgi fragmentation and neuronal degeneration.
SOD1 is an antioxidant enzyme that catalyzes the conversion of O2 to H2O2 and maintains the homeostasis of intracellular reactive oxygen species for detoxification purposes. Studies have found that the accumulation of insoluble proteins found in patients with SALS and FALS is immunoreactive SOD1, and its misfolding and protein aggregation are closely related to ALS. The SOD1 gene after mutation induces excessive free radicals. The toxic effect of free radicals, and mutational SOD1 aggregation, forms a high molecular weight insoluble complex, which ultimately leads to the death of motor neurons.
AD is a common neurodegenerative disease characterized by progressive dementia in the elderly. One of the typical pathological features of AD is the formation of a large number of senile plaques (SP), mainly caused by Aβ accumulation. Aβ in the brain is a polypeptide which contains 39-43 amino acid . It is produced by proteolysis of amyloid precursor protein (APP). As a transmembrane protein, APP is widely distributed in various tissues in the body, and has the highest expression in the brain. The normal operation of the Golgi apparatus is required for the transport, formation, classification and processing of APP and its secretase. The route of APP is from the endoplasmic reticulum to the Golgi body and then to the plasma membrane. For example, the formation of APP can produce Aβ, which may occur in the late Golgi and secretory pathways. If the Golgi transport function is impaired, it may affect the normal transport of APP and cause Aβ accumulation. At the molecular level, accumulation of Aβ causes Ca2+ influx, the process will activate calpain, and then increases the cleavage of P25-P35. Finally, P25 activates cdk5. Activated Cdk5 phosphorylates GRASP65, which ultimately leads to the fragmentation of the Golgi.
The typical pathological feature of AD is the formation of eurofibrillary tangles (NFTs), the main component of which is hyperphosphorylated tau protein. Tau protein is a microtubule-associated protein with the highest neuron content. Its main function is to promote microtubule synthesis and stabilize microtubules. It plays a role in maintaining the cytoskeleton and acts as a transprotant pathway for organelles, vesicles, proteins and signaling molecules, mostly localized in neuronal axons. Interesting, studies have found that the increase in Golgi fragmentation is age-related and is associated with hyperphosphorylation of Tau protein. Further studies find that Golgin-84 triggers hyperphosphorylation of the Tau protein by activating cdk5 and an extracellular signal-regulated kinase, which in turn induces Golgi fragmentation. Eventually triggers neuronal death and induces AD.
The research also offers yet another excellent example of how studying rare diseases helps to advance our fundamental understanding of human biology. It shows that helping those touched by Batten disease can shed a brighter light on basic cellular processes that drive other diseases, rare and common.
Batten disease affects about 14,000 people worldwide [2]. For those with the juvenile form of this inherited disease of the nervous system, parents may first notice their seemingly healthy child has difficulty saying words, sudden problems with vision or movement, and changes in behavior. Tragically for parents, with no approved treatments to reverse these symptoms, the disease will worsen, leading to severe vision loss, frequent seizures, and impaired motor skills. The disease can be fatal as early as late childhood or the teenage years.
Batten disease also goes by the more technical name of juvenile neuronal ceroid lipofuscinosis. Using this technical name, it represents one of the more than 70 medically recognized lysosomal storage disorders.
These disorders share a breakdown in the ability of membrane-bound cellular components, known as lysosomes, to degrade the molecular waste products of normal cell biology. As a result, all this undegraded material builds up and eventually kills affected cells. In people with Batten disease, the lost and damaged cells cause progressive dysfunction within the nervous system.
They then identified all the other proteins that interact with the CLN3 protein in the Golgi body and elsewhere in the cell. Their data showed that CLN3 interacts with proteins known for transporting other proteins within the cell and forming new lysosomes.
That gave them a valuable clue: the CLN3 gene must be a player in these fundamentally important cellular processes of protein transport and lysosome formation. Among the proteins CLN3 interacts with in the Golgi body is a particular receptor called M6PR. The receptor known for its role in recognizing lysosomal enzymes and delivering them to the lysosomes, where they go to work inside these bubble-like structures degrading cellular waste products.
The researchers found that loss of CLN3 led this important M6PR receptor to be broken down within lysosomes. The breakdown, in turn, altered the normal shape of new lysosomes, and that limits their functionality. The researchers also showed that restoring CLN3 in cells that lacked this gene also restored the production of more functional lysosomes and lysosomal enzymes.
Most of all, this paper demonstrates the power of basic research to define needed molecular targets. It shows how these fundamental studies are helping families affected by Batten disease and supporting their love, hope, and quest for a cure.
I-cell disease (mucolipidosis II) is a rare inherited metabolic disorder characterized by coarse facial features, skeletal abnormalities and mental retardation. The symptoms of I-cell disease are similar to but more severe than those of Hurler syndrome. The symptoms associated with this disorder typically become obvious during infancy and may include multiple abnormalities of the skull and face and growth delays.
This disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Multiple enzyme deficiencies associated with I-cell disease lead to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.
I-cell disease is caused by a mutation in the GNPTA gene that leads to a deficiency in the enzyme UDP-N-acetylglucoseamine-1-phosphotransferase. I-cell disease is inherited as an autosomal recessive genetic trait.
Some of the physical features associated with I-cell disease (ML II) may be apparent at birth (congenital), whereas other features may become apparent between the ages of 6 to 10 months. Craniofacial abnormalities may include coarse facial features, a depressed nasal bridge, a long and narrow head, an unusually high and narrow forehead, and/or skin folds on the inner corners of the eyes (epicanthal folds). The skin may appear to be unusually thick and tight in certain areas of the body (e.g., face, arms, and legs). The corneas of the eyes may appear cloudy.
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