A Link Between Genetics And Gangliosidosis

Some of the general symptoms of the disease can be characterized by hind limb spasticity, weight loss, tremors, abnormal posture with lordosis, and possibility of visual impairment. Muscle weakness, clasping of the limbs, and myoclonic twitches of the head that can be onset late in the disease. Research of the GM2 ganglioside has revealed that storage of the fatty substance varies a large

The specific enzyme beta-hexosaminidase A is responsible for catalyzing the biodegradation of acidic fatty material in the brain and spinal cord known as gangliosides.

The HEXA gene provides instruction for making part of an enzyme called beta-hexosaminidase A, which plays a very critical role in the brain and spinal cord. This enzyme is found in the lysosomes, which are the structures in cells that break down toxic substances and their job is that of a recycling center. Beta-hexosaminidase A helps break down a fatty substance called GM2 ganglioside. The mutations in the HEXA gene disrupt the activity of beta-hexosaminidase A, which prevents the enzyme from breaking down GM2 ganglioside. As a result, this substance accumulates to toxic levels, particularly in the neutrons in the brain and also the spinal cord. Damage by the buildup of GM2 ganglioside leads to the destruction of the neurons; Causing signs and symptoms of Tay-Sachs disease.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most widespread age-related neurodegenerative diseases. Both diseases impact a considerable number of people, where AD occurs in around 10 percent of the population greater than the age of 65 while PD occurs in roughly 1 percent of the population above the age of 65. AD is considered to be the most widespread cause of dementia, characterised by the progressive memory and cognitive deficits which impair ones day to day activities. The pathological hallmark of AD comprises of extracellular accumulation of senile plaques consisting of mainly amyloid-beta (Aβ) peptides, along with neurofibrillary tangles which are composed of the phosphorylated tau protein, located in the hippocampus and cortex. Conversely, PD is considered to be the most widespread movement disorder that is characterised by symptoms such as rigidity slow movements, resting tremor and other instabilities. The extreme loss of dopaminergic neurones in the substantia nigra is what defines PD, as the loss of this nerve cell can be linked to Lewy bodies containing aggregates of a soluble protein called α-synuclein.

Fig. 1 Shows the action of Hex A cleaving the GalNAc off of the GM2 ganglioside and converting it to the GM3 ganglioside. This is the blocked reaction in Tay-Sachs disease. (GalNAc=N-acetylgalactosamine; Gal=Galactose; Glc=Glucose; Cer=Ceramide; NANA=Sialic Acid ) [ 6 ]

In general, each neuron releases a single type of neurotransmitter. Neurons that release the neurotransmitter acetylcholine are called cholinergic neurons and degeneration of cholinergic neurons in the brain are associated with Alzheimer’s (Sherwood). Drugs classified as short-term cholinesterase inhibitors are used to treat Alzheimer’s because the drugs prolong the effect of acetylcholine. There are special cells called microglia that are associated with Alzheimer’s disease as well. Microglia are immune defense cells in the CNS (central nervous system) or brain and spinal cord. The remove foreign and degenerate material in the CNS. Overactive microglia appear to be involved in a variety of inflammation-related disorders like Alzheimer’s (Sherwood). Inflammation is triggered by the body’s immune system and is a factor that plays in the progression of the disease (Alzheimer’s Disease & Dementia).

These clumps are found in the fatty membrane that covers nerve cells and result in the interruption of signals between synapses, which are the areas between nerve cells where information passes through. If these signals are interrupted, it can become very difficult for this information to be processed. This discovery has given scientists the idea, that perhaps this is the primary cause of Alzheimer’s Disease.

The brain is composed of billions of neurons, which interact and connect with each other, which allow us to perform our everyday activities. Plaques and tangles are the two structures that are suspected for the damage of nerve cells. Plagues are deposits that build up between neurons and tangles build up inside the neurons. Most people develop these abnormal obstructions as they age, but those with Alzheimer’s have a tendency to develop much more.

Gaucher Disease is a type of lysosomal storage disorder. The importance is that they are meant to keep everything in order. Lysosomes are microscopic organelles that have a primary function to serve as digestion compartments. According to Davidson, (1) “lysosomes help break down many different materials such as fats, proteins, waste products, and more to transfer those compounds to become new cell building materials”. Consequentially, making lysosomes an important factor to our daily functions in life.

Tay Sach’s disease results in an accumulation of lipids in the brain’s nerve cells. The underlying cause of Tay-Sachs disease is a mutation in a gene that codes for a lytic enzyme known as Hexosaminidase A (Hex A). Tay-Sachs as well as other lipid storage diseases are incurable, but we believe that gene therapy has the potential for widespread correction of the lipid storage defect in humans by means of the cross-correction cellular pathway. The vehicle of transportation for the functional copy of the gene is a modified version of the Adenovirus. An advantage of the adenovirus is that its genome does not integrate into the host genome to transcribe its

Description: Alzheimer’s disease is a disease that attacks the brain’s neurons resulting in loss of memory, skills, and normal behaviors. The affected neurons produce the neurotransmitter, acetylcholine. However, when affected by the disease, acetylcholine connections break and kill the cells. The location of the dying neurons correspond with the symptoms that appear. The most obvious example of this would be the dying of neurons in the hippocampus. The hippocampus is the part of the brain responsible for short term memory. Once the neurons inside the hippocampus die, a patient with Alzheimer’s will not be able to make new memories. Along with the dying of neurons, another cause can be plaque and tangles in the brain. Beta-Amyloid plaque

Gaucher disease is an autosomal recessive disease that occurs in about 1 in 20,000 births. It is one of the highest prevailing Lysosomal Storage Disorders and it involves many organs including but not limited to the spleen, liver, brain, lungs and bone marrow. In the lysosomes part of the cell the enzyme glucocerebroside does not work properly allowing it to build up toxic levels in the various different organs. It is an inherited genetic disorder so in order for a child to be born with it, both parents must give the child a copy of the mutated gene. It was first discovered by Dr. Philippe Gaucher in 1882, hence the name Gaucher disease.

The first mode of action is when galectin-8 is in a high concentrations or when it is overexpressed. This induces the accumulation of p21. The next mode of action is when it is in the presence of selected growth factors and therefore immobilized. In this mode, galectin-8 has interactions with high affinity receptors. These interactions promote cell adhesion, cell spreading, and cell migration [6]. The last mode of action takes place under the conditions that there is no p21 or after continual lack of growth factors. This is when apoptosis takes place [6]. All three of these modes of action are controlled by different signaling pathways

An amyloid plaque is finding between the brain cells. It forms when protein pieces called Bata-amyloid- clump together. They come from large protein from fatty membrane around nerve cell. Beta-amyloid is chemically “stinky” and builds up into plaques. For a long time scientist thought that plaques might cause all of the damage to neurons that is seen in the Alzheimer disease. But now many scientists think that oligomers may be a major culprit. The other group also thinks that plaques might be a late stage of attempt by brain to get this harmful beta-amyloid away from neurons.

The brains of people with Alzheimer’s disease have an abundance of two abnormal structures – amyloid plaques and neurofibrillary tangles. These are made of misfolded proteins which can stick together with other misfolded proteins to form insoluble aggregates. If these aggregates build up, they can disrupt cellular communication and metabolism. The third main feature of Alzheimer’s is the loss of connections between cells leading to the ill-functioning and death of cells (Institute and Aging, 2011).