Peroxisome Organelle Study Eukaryotic cells are very large and complex structures that contain many different types of organelles that have specific jobs to help keep the cell stable and functioning. Nearly every eukaryotic cell contains multiple peroxisomes which are small membrane­enclosed spheres similar to the structure of lysosomes. Peroxisomes are also similar to the organelle mitochondria and chloroplasts in the way they replicate by division (Cooper, 2011). Peroxisomes are important for the cell because they contain one or more enzymes that are used to oxidize different types of organic substances (Vamecq, 2014). Peroxisomes are able to oxidize substances such as amino acids, fatty acids, and even toxic substances such as alcohols (Vamecq, 2014). The enzymes peroxisomes use to break down these substances also produce hydrogen peroxide as a by­product which can be dangerous to a cell. To handle this hydrogen peroxide the peroxisomes have a built in enzyme catalase which is able to decompose the hydrogen peroxide into water, or use the hydrogen peroxide to help oxidize other compounds (Cooper, 2011). This built in response will protect the rest of the cell from any toxic effects. One of the large roles of peroxisomes is the action of lipid biosynthesis, in which different fatty acids are able to be oxidized. In animal cells cholesterol is able to be synthesized by peroxisomes from fatty acids and in the liver produce bile acids from the cholesterol (Vamecq, 2014). Peroxisomes are even able to help with the synthesis of certain phospholipids used for membrane structure in tissues such as the heart and brain (Cooper, 2011). In plant cells, peroxisomes are stored in seeds to help with the conversion of fatty acids into carbohydrates when the seed requires energy needed to grow (NIH, 2010). Another role of peroxisomes in plants is helping with photorespiration within the leaves. When CO​
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converted into carbohydrates during photosynthesis certain by­products can be produced that are not needed for the cells so they are presented to the peroxisomes to be converted into glycine or glycerate, which eventually will be reused in the photosynthesis process (NIH, 2010). The simple structure of peroxisomes is composed of a plasma member lipid bilayer containing all the necessary enzymes for oxidizing with a crystalline core at its center. Peroxisome assembly is very similar to mitochondria and chloroplasts which do not involve the endoplasmic reticulum, golgi apparatus, and lysosomes (Cooper, 2011). The new material needed for production of peroxisomes is made outside of the peroxisome and transferred into the organelle so it can replicate itself (Cooper, 2011). Proteins needed are produced by the ribosomes and transported into peroxisomes as polypeptide chains and phospholipids needed for the membrane are transported via transfer proteins (Cooper, 2011). Once the peroxisome has gathered enough material and grown, it will divide itself so two fully functioning peroxisomes now exist. Peroxisomes were first discovered in 1954 by J. A Rhodin a Swedish Graduate student. It wasn’t until the late 1960’s that Rene de Duve a Belgian cytologist and biochemist coined the term peroxisome because they produce and reduce hydrogen peroxide. Zellwegger’s disease was first studied in the 1964 Bowen’s study out of John Hopkins and from the University of Iowa Hospital. This study involved four children from two families that showed multiple congenital defects. Two of the siblings of a child in the study died within two weeks of birth. It was first called cerebro hepato­renal syndrome and was coined by Passagea and Mac Adams (1967). This study was done in Cincinnati and 5 children were diagnosed with cerebro hepato­renal syndrome.(Zellweger, 1987) Zellweger’s disease was named after Hans­ Ulrich Zellweger a pediatrician that contributed much of his research to cerebro hepato­renal syndrome. He was born in Switzerland in 1909 and received his doctorate from Zurich. He later went on to become a professor of pediatrics at University of Iowa where he founded one of the first clinical cytogenetic laboratories in the US. Through his research in his Iowa Muscle Clinic and other clinics throughout the state Zellweger was able to study many neuromuscular disorders as well as dysmorphic syndromes. (Wiedemann, 1991) Zellweger syndrome is one of three peroxisome biogenesis disorders of the Zellweger spectrum. This includes: Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). These 3 diseases were once thought of one distinct disorder, but are now categorized into the same disease spectrum. Zellweger syndrome is the most severe disease, and IRD is the least severe form (GHR, 2010). Individuals with Zellweger syndrome typically develop symptoms during their first year of life. Infants will experience hypotonia (loss of muscle tone), hearing and vision problems, seizures, etc. These symptoms are majorly due to hypomyelination, a reduction in central nervous system myelin. Myelin is critical for normal CNS functions, serving to insulate nerve fibers in the brain and promoting efficient transmission of nerve impulses. The destruction of the myelin also leads to the loss of white matter (leukodystrophy). The loss of myelin and white matter affects intellectual disability and also causes respiratory problems (Karimi, 2006). Affected individuals will develop what is known as chondrodysplasia punctata. It impairs the normal development of skeletal bones, leaving large spaces between bones of the skulls and other bones that can be seen through the X­ray. This results in distinctive facial features such as a high forehead, hypoplastic supraorbital ridges, epicentral folds, mid face hypoplasia, and large fontanels (GHR, 2010). Although the molecular basis for the cause of Zellweger spectrum disorders is debated to be unknown, it is strongly correlated with mutations on the peroxisomal biogenesis factor (or PEX) genes. To date, there are known mutations on 12 of the PEX genes that produce phenotypic symptoms of Zellweger spectrum disorders. The PEX genes are on chromosome seven of the human genome and the mutations are autosomal recessive (NIH, 2010). The spectrum ranges from complete absence of peroxisomes to single protein deficiencies, which explains the variety of symptoms in patients exhibiting Zellweger spectrum disorders. Biochemical testing has shown to be highly effective in testing for the mutations. In most cases, the these mutations are first detected with an over accumulation of very long chain fatty acids (VLCFA) in the plasma (Levesque, 2012). The two most common mutations occur on the PEX 1 gene, who's 67 identified mutations account for 70% of all Zellweger syndrome patients (NIH, 2010). Because of the sheer number of mutations that could account for Zellweger patients, testing is usually done when an unusually high number of cases occur in a population, often due to a founder effect (Lee, 2013). Such an example of a potential founder effect was studied by Levesque in a small region of Ontario, Canada called Sageny­Lac­St­Jean. In this region, there is a 1/12,191 occurrence of Zellweger disorders compared to the US average of 1/50,000 live births and 1/500,000 in Japan (Levesque, 2012). In this particular case, 5 patients in 20 years (1990­2010) were isolated all with mutations on the less common PEX 6 gene. It was predicted to have a frame shift which deleted some PEX 6 proteins involved in peroxisomal activity. There is much more to be studied on the genetic mutations of PEX genes, but their rarity and sometimes seemingly randomness of these mutations make this a very difficult area of research, yet very active. No cure currently exists for Zellweger’s syndrome. Currently, treatment consists of symptomatic treatment in order to alleviate suffering. This includes gastronomy for proper feeding, cataract removal, vitamin supplementation, monitoring for hyperoxaluria, epileptic medication, and bile acid therapy (Steinberg et al., 1993). Arai et al. conducted research in order to determine whether DHA supplementation and synthetic oil administration would decrease the amount of very long chain fatty acids (VLCFA) in the plasma. Lorenzo’s oil, consisting of glycerol trioleate and trierucate oil, and RBC DHA supplementation was administered at different time points to four female patients with Zellweger’s syndrome. The oil competes for elongase, an enzyme required for VLCFA synthesis; the study found that earlier administration of the oil resulted in a decrease of VLCFA in the plasma (Arai et al., 2008). Administration of DHA resulted in an increase in liver and brain DHA levels in some patients as well. VLCFA accumulation leads to neurological deficits in patients with this syndrome and lack of DHA results in membrane permeability, thus supplementation of the two may alleviate some symptoms associated with the disease (Arai et al., 2008). Tanaka et al. found similar results in their study of Lorenzo’s oil and DHA supplementation, yielding decreased symptoms of liver dysfunctions and neurological deficits in the infants (Tanaka et al., 2007). Further research with a larger sample is necessary in order to determine the exact pathways involved and initiate a treatment plan for those suffering from Zellweger’s syndrome. References Arai, Y., et al., ​
Effect of dietary Lorenzo's oil and docosahexaenoic acid treatment for Zellweger syndrome.​
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(4): p. 180­182. Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000 Genetics Home Reference (2010). ​
Your Guide To Understanding Genetic Conditions. Available from http://ghr.nlm.nih.gov/condition/rhizomelic­chondrodysplasia­punctata Lee, P.R., Raymond, G.V. (2013) Child Neurology: Zellweger syndrome. ​
Neurology 80(20): 207–210. Levesque, S., Morin, C., Guay, S.P., et al. (2012) A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population. BMC Med Genet 13:72 National Institute of Health (2010). ​
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Available from http://ghr.nlm.nih.gov/gene/PEX1 R Karimi, T Brumfield, F Brumfield, F Safaiyan, S Stein. ​
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