The Causes Of Lysosomal Diseases

It is a condition that has a complete deficiency of the hexosaminidase-A (HEXA) enzyme. There are over 120 mutations of the HEXA gene that cause the disease, because the mutations reduce or eliminate activity of the beta-hexosaminidae-A enzyme. The HEXA enzyme is essential for the process of hydrolysis of GM2 ganglioside to take place. The hydrolytic HEXA enzyme, in a healthy individual, plays a large part in the process of breaking down glycolipids in the lysosomes of the cell. With the aid of other enzymes in the cell, the HEXA enzyme is responsible for the breakdown of specific fatty acid derivatives called gangliosides. For individuals with Tay-Sachs disease that lack the HEXA enzyme, the fatty substance of the GM2 ganglioside begins to accumulate in the

Similarly, an increase in the levels of lipid peroxidation was observed in Aβ-induced rat hippocampal cells, confirming previous reports [17]. Enzymatic antioxidants such as SOD, catalase, and GPX act as the cellular antioxidant defense mechanism against free radicals. Since NADPH is required for the regeneration of catalase from its inactive form, catalase activity might be decreased in Aβ induced toxicity due to reduced NADPH levels. In this study, we have reported that Honokiol treatment significantly increased the enzymatic antioxidant activities in APP-CHO cells. In addition, non-enzymatic antioxidants like GSH also exhibited beneficial neuroprotective effects against oxidative stress. GSH is an endogenous nonenzymatic antioxidant that prevents damage to cellular components caused by ROS such as free radicals and peroxides. GSH is oxidized to glutathione disulfide (GSSG) by ROS, thereby causing a reduction in the level of GSH. GR reduces GSSG to GSH via NADPH, which in turn is released by glucose-6-phosphate dehydrogenase [18]. Honokiol treatment upregulated the activity of these antioxidants in APP-CHO cells. In addition to oxidative stress, a strong association between insulin resistance and the development of AD has been demonstrated. Several studies have reported that insulin resistance (IR), an underlying characteristic of type 2 diabetes, is an important risk factor for AD

Within the foetus, embryonic nerve cells grow exponentially, then migrate to their destinations and develop into a vast collection of distinctive neuronal cell categories unique to their specific function. In prearranged patterns, the cells later form networks with other brain cells. The metabolic process of alcohol instigates makes the cells vulnerable to cell damage by free radicals (harmful substances). Research has suggested that “free radical damage can kill sensitive populations of brain cells at critical times of development in the first trimester of pregnancy (Cartwright, M.M).” Additional experiments have suggested that the third trimester is a particularly susceptible stage for damage to brain cells linked to FASD. The metabolic breakdown of alcohol interferes with brain development through the alteration of the function or production of natural regulatory substances that assist in the promotion of the differentiation and orderly growth of

“Without Hex-A, a fatty substance, or lipid, called GM2 ganglioside accumulates abnormally in cells, especially in the nerve cells of the brain. This ongoing accumulation causes progressive damage to the cells.”http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024672/

Background Research: Cellular Respiration is used by the cells to make ATP, by releasing chemical energy from sugars and other carbon based molecules. There are 3 stages to Cellular Respiration, Glycolysis, Krebs Cycle, and the Electron Transport Chain. The inputs of Glycolysis are 2 ATP’s, a Glucose molecule, and a Pyruvate. The inputs for the Krebs Cycle are oxygen, and. In animals, energy is consumed by eating food. In that food they eat, Glucose is found and broken down by the process of cellular respiration, which then converts into energy known as ATP. When there is a lot of ATP and Glucose, the liver converts it into glycogen.

A cohort of mice underwent a second mTBI after 24 hours. Mice from both WT and Tg groups were assessed 2 days, 9 weeks, and 16 weeks after mTBI treatment. Primarily, H&E stain was employed along with Gomori’s iron stain to localize site and severity of mTBI injury. The degree of A deposition in the somatosensory cortex (SSC), the perihippocampal cortex (PHC), and the hippocampus (HP) of both hemispheres was determined by 4G8 immunostaining. In addition, GFAP staining was used to quantify the population of astrocytes at the site of the injury. Furthermore, Sandwich ELISA was utilized in mice groups 16 weeks after injury to measure A40 and A42 peptide levels in various brain regions, including the cerebral cortex, the hippocampus, and the cerebellum. Such tissues were also analyzed for isoprostane levels that are produced by lipid peroxidation. Isoprostanes were also detected in urine samples at various survival periods. Moreover, mice underwent Morison water maze (MWM) and composite neuroscore (NS) tests at 16 weeks’ post-injury to examine cognitive and motor functions respectively. Uryu and collegues found a significant increase in iron deposits and reactive astrocytes in the repetitive mTBI postmortem sections of Tg mice, when compared to other groups at 16 weeks after the injury. This was not the case in WT mice. Similarly, there was a significant increase in the A burden within select brain regions (i.e. SSC, PHC, HP) of single and

The central nervous system finds an alternative source of energy derived from fatty acids. This energy comes for the process of lipolysis in adipose tissue. Lipolysis it is the brake down of triglycerides that produces a glycerol and three fatty acids. These fatty acids are converted to acetyl CoA. In the liver, ketone bodies are produced from the over production of acetyl CoA (2). The liver produces ketone bodies because it can no longer metabolize acetyl CoA in the Krebs cycle to provide energy. As the fuel source, ketones flow from the liver into the blood which transports them where energy is required. Once they reach their destination, such as the brain of skeletal muscles (2), they are converted back into acetyl CoA and produce energy through the Krebs cycle. Because ketones are lost in urine due to the Krebs cycle not having enough intermediate oxaloacetate, low amounts of energy are available. Even though ketone bodies provide energy for the body, some processes still need glucose. The glycerol derived from lipolysis can be used to make pyruvate and, ultimately, glucose through

The liver plays a central role in the nitrogen metabolism in the body. The nitrogen transport is performed mainly from muscle and lung to the liver, as glutamine, plus alanine and aspartate. The breakdown of glutamine releases NH3 that through mitochondrial enzymes comes as a substrate in the urea cycle, producing urea and ornithine. In the kidney, the action of glutaminase produces the NH3, because that glutamine is quantitatively the most important donor of NH3 in this tissue. In collecting tubule NH3 combines with exported H+ to form NH4+, which is lost in the urine. Thereby, glutamine metabolism is essential for acid-base buffering [33], and also plays an important role in the biosynthesis of nucleotides, detoxification of ammonia, glutathione

(CNPase), glutathione S-transferases pi (GSTpi), brain-derived neurotrophic factor (BDNF), and the transcription (CNPase), glutathione S-transferases pi (GSTpi), brain-derived neurotrophic factor (BDNF), and the transcription

As previously mentioned the brain is enriched with polyunsaturated fatty acids, particularily DHA and the omega-6 AA. While the brain can synthesize saturated and monounsaturated fatty acids, it must rely on uptake of either the preformed DHA and AA or their dietary precursors, which can be converted to DHA and ARA within the brain. While the brain does have the capacity to synthsize DHA its rate of synthesis relative to uptake from the plasma is relatively low suggesting that uptake from plasma and not synthesis within the brain is the major source. Furthermore, while the liver can upregulate its ability to synthesize DHA especially under conditions of low dietary omega-3 intake, the brain does not upregulate DHA synthesis under these conditions.

Lipid-induced muscle insulin resistance plays a critical role in the pathogenesis of type 2 diabetes. A cellular mechanism of this lipid-induced muscle insulin resistance has yet to be discovered. The Randle model proposes lipid oxidation raises mitochondrial [acetyl-CoA]/ [acetyl CoA] and [NADH]/[NAD+] ratios. This is because acetyl-CoA and NADH are allosteric inhibitors of pyruvate dehydrogenase complex (PDH). PDH converts pyruvate into acetyl-CoA, thus linking the processes of glycolysis and citric acid cycle. Acetyl-CoA derived from fatty acid produces citrate, which inhibits the glycolytic enzyme phosphofructokinase. Thus, increased fatty acid oxidation reduces glycolytic flux and prevents muscular glucose uptake and leads to impairment

However, high rates of glycolysis are only possible if there is a constant supply of oxidized nicotinamide adenine dinucleotide, commonly referred to as NAD+, which can be achieved by lactate dehydrogenase converting pyruvate to lactate. Increased lactate concentration within the astrocyte causes lactate to be pumped out into the extracellular space. The ANLS hypothesis proposes that this lactate is shuttled into the neurons to enable them to maintain the tricarboxylic acid cycle whose products enable mitochondrial oxidative phosphorylation to continue. The ATP produced in the mitochondria is used to sustain Na+/K+ ATPase at the cell membrane to enable continued depolarization and sustained excitatory post-synaptic potentials from the glutamate stimulation. Further, for the astrocyte to maintain glycolysis, uptake of glucose from surrounding blood vessels is greater in astrocytes, relative to neurons.

The second pathway is not completely independent from the first,as in this, the Amadori product (fructosamine) reacts with oxidative agents, like hydroxyl radicals, and undergoes modifications that lead to the formation of carboxymethyllysine (CML), one of the main AGEs (Ahmed et al., 1986, Booth et al., 1997, Thorpe and Baynes, 2003). The hydroxyl radicals can be produced either by transition metal-catalysed oxidation or by glucose autoxidation (Hunt and Wolff, 1991). This close interaction between glycation and oxidation leads to the development of the term glycoxidation, which describes the fact that AGEs are produced mostly from the interaction of these two processes (Baynes, 1991). Although indications and potential mechanisms are in place to suggest an active involvement of oxidative stress in protein glycation in normoglycaemia and hence the increase in the risk of chronic diseses, so far little evidence is available to support such a hypothesis.

A/the central regulator of GSH homeostasis, hence redox balance mitigation of neuron apoptotic death [5], is the master transcription factor, nuclear factor E2-related factor 2 (Nrf2). Nrf2 regulated genes include glutamate-cysteine ligase (GCL) (rate limiting enzyme in GSH synthesis), glutathione reductase (generation of reduced/active GSH), and multiple components of the gamma glutamyl cycle by which the GSH synthesis substrate, Cys is supplied to neurons in addition to dietary source(s) [20, 25]. Previous study in our laboratory addressed Nrf2/ARE (Antioxidant Response Element)-mediated neuroprotection which should prevent neuron death by maintaining GSH homeostasis [7]. E does up-regulate Nrf2 and the knockout of Nrf2 illustrated that this increase in Nrf2 confers a certain degree of neuroprotection [7]. However, somehow E prevents Nrf2 from providing complete protection and a population of fetal neurons still succumbs unless we artificially increase Nrf2 beyond its innate capacity [7].

The disorders caused by lipid metabolism enzyme deficiency is due to the metabolite accumulation in the cell and parts of the bodies. The major diseases are Gaucher’s, Fabry’s, Tay-Sachs and Niemann-Pick disease. Gaucher’s occurs due to the accumulation of glucocerebrosidase leading to neurological phenotype in some cases and enlarged liver and spleen and bone abnormalities in other cases. Tay- Sachs involves the buildup of gangliosides in tissues, which leads to intellectual disabilities, dementia, paralysis and blindness in different cases. Neimann-Pick involves the buildup of sphingomyelin, leading to neurological issues. Fabry’s involves accumulation of glycolipids in tissues, leading to poor vision, kidney failure or heart failure,