4. 1 Functional Classifications Of Functional Functions

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.

Neurodegenerative diseases continue to affect the lives of millions Americans each year, with incidence and prevalence rates ever increasing. These diseases cause degeneration or death of nerve cells in the brain. These diseases can cause a financial and emotional burden on not only patients themselves, but also family members and care givers as well. Molecular mechanisms that underlie these diseases have remained relatively unclear, despite much research. Understanding the mechanisms of these diseases are facilitated by utilizing model organisms to study pathways involved in neurodegenerative diseases. One such model organism is the Caenorhabditis elegans nematode. The C. elegans roundworm has displayed usefulness as a template to study neurodegenerative diseases in humans, including Parkinson’s disease and Alzheimer’s disease.

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

Since mature autophagosome fuse with lysosomes to become autolysosome in the very late stage of autophagy, we asked whether miR34a could retard autophagosome-lysosome fusion by examining the co-localization of EGFP-LC3 and LysoTracker Red, a specific dye for live cell lysosome labeling [47]. As expected, EGFP-LC3 puncta were dramatically reinforced in miR34a mimic transfected cells but did not co-localize with LysoTracker Red. This was acting similar to cells treated with bafilomycin A1 (Baf), which blocked autophagosome-lysosome fusion. In contrast, E64D treatment induced a remarkable increased EGFP-LC3 puncta, which were well co-localized with LysoTracker Red (Fig. 1D). Since lysosome-associated membrane glycoprotein 2 (LAMP2) is also critical for autophagosome-lysosome fusion [48], we examined the effect of miR34a on LAMP2 expression using WB analysis. MiR34a caused an unexpected increase of LAMP2 (Supplementary Fig. 1C), suggesting that the mechanism by which miR34a blocked autophagosome-lysosome fusion was not due to LAMP2. As LAMP2 is mostly important for chaperone mediated autophagy, its increase might be a compensation for the decrease in macroautophagy. In summary, the above results reinforce that miR34a compromised Aβ degradation by, at least, blocking autolysosome formation.

Besides the appearance of episodic focal inflammatory lesions, there is a more generalized and progressive disease process that results in slow axonal , neuronal degeneration and subsequent accumulation of neurologic disabilities. The pathogenesis of this neurodegenerative process is aurged to the mitochondrial dysfunction which could be a key contributing mechanism ( Su et al., 2013)

Multiple System Atrophy (MSA) is an adult onset progressive neurodegenerative disease, characterized by various degrees of Parkinsonism, cerebellar ataxia, and failure of the autonomic nervous system. MSA is classified as a α-synucleinopathy, a subset of neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein (α-Syn) in the CNS (Fellner et al., 2011; MartÌ et al., 2003). In MSA, α-syn aggregates appear primarily as glial cytoplasmic inclusions (GCIs) in oligodendrocytes (Wakabayashi et al., 1998). The accumulation of α-syn aggregates is associated with glial pathology and neuroinflammation in MSA and other α-synucleinopathies such as, Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) (Fellner et al., 2011). Microglia activation has also been implicated in α-synucleinopathies as well as other neurodegenerative disorders including Alzheimer’s disease (AD) and Multiple Sclerosis (MS) (Fellner et al. 2011; Minagar et al., 2002).

Since the protein does not disintegrate, it amasses into neuritic plaques (The Alzheimer's Project, 2009). The neurofibrillary tangles structure inside neurons and are made out of matched helical fibers, neuropil strings and dystrophic neuritis. Nfts cause the breakdown of the vehicle framework, as tau protein tumbles off and starts to cluster together, framing tangles, irritating the correspondence between neurons, prompting neuronal demise showed through dementia. The neuropathological criteria for an AD analysis are focused around the recurrence of the decrepit plaques and the geography of the neurofibrillary tangles (Goetz, 2007). The cerebrocortical decay prompts the decrease of the mind with twenty percent or more. The

SMER 28 is a new small-molecule enhancer of the cytostatic effects. The target of rapamycin proteins has been reported to be able to regulate various cellular processes including autophagy, which may play a protective role in some neurodegenerative and infectious diseases.

Niemann-Pick’s disease Type C (NPC) is disease in which unesterified cholesterol and other lipids accumulate in late endosomes/lysosomes (LE/L) of all cells and tissues. Resulting in excessive amounts of cholesterol accumulation within the liver and spleen and excessive amounts of other lipids accumulating in the brain. The cause of NPC is quite distinct from A & B whose patients have defects in their lysosomal acid sphingomyelinase gene (3). On the contrary, NPC is a recessive, autosomal disorder that affects around 1 in 150,000 births and causes premature death due to relentless neurodegeneration as well as lung and liver dysfunction (4,5). NPC can further be divided into two subgroups known as C1 and C2, which are each, caused by a different gene mutation.

VPS35 is a gene that plays a huge role in the membrane protein-recycling retromer complex. There are three genes that are known to be associated with Parkinson’s disease, SNCA and LRRK2, which are similar to each other, and one that is different. VPS35 is the third gene associated with Parkinson’s disease that causes an increase in the degrading of DML 1 complexes. The authors of this article want to know why mutation of the VPS35 gene leads to neurodegeneration. The researchers used mice for their experiment that housed the VPS35 mutant gene.

One of the most important properties of BBB is that it separates the brain tissue from the blood circulation of the CNS. By that it consists of three parts: the layer of endothelial cells connected through tight junctions, basal membrane, and astrocytes and pericytes. Its main function is it only select molecules to pass from the bloodstream into the fluid that bathes the brain, whereas vital nutrients get in, toxins and pathogens are blocked. Formed by endothelial cells and epithelial cells and contributing to the intercellular tight junction, BBB is the creation of a paracellular barrier for ions, proteins and other solutes. The brain has to think a lot and do a lot of extracting necessary ingredients such as oxygen and glucose in order for us to function and live and to do some activity movements. Transporting proteins and drug delivery is one of those mechanism of the BBB in which it allows important substances to pass through into the brain and spinal cord preventing a blockage of certain materials into the CNS.

Alzheimer’s disease is the leading form of dementia within the world’s elderly population and given that there exists an ever increasing percentage of the elderly population within society, understanding this neurodegenerative disease has become more important than ever. It is a disease associated with subcortical temporal lobe structures such as the Hippocampus, the Entorhinal Cortex, the Amygdala, the Thalamus, among others. Clinically, those millions of individuals suffering from the disease experience episodes of irreversible memory loss, changes in personality and confusion (among a plethora of other symptoms). Physiologically, the disease is characterized by the accumulation of insoluble amyloid beta plaques, derived from the amyloid precursor protein (APP). Another characteristic marker for Alzheimer’s dementia is the Hyper-phosphorylation of the Tau protein which then aggregates to form insoluble neurofibrillary tangles (NFTs), that inhibit a cell’s ability to regulate the stabilization of the microtubule component tubulin.

Recently, two strains of human SOD1 were isolated and expressed in transgenic mouse models, which resulted in ALS progression accompanied by the propgation of the SOD1 aggregates from the spinal cord to the brainstem (Bidhendi et al., 2016). Additionaly, several studies have identified a Q/N-rich prion-like domain in the TDP-43 C-terminal sequence composed of glutamate and aspartate rich regions that are susceptible to aggregation (Bozzo et al., 2016; Cirulli et al., 2015; Kitamura et al., 2016; Wei, Yuanyuan et al., 2016). Cleavage of TDP-43 prion-like domain yields a truncated TDP-25 fragment that is less prone to aggregation when accompanied with TDP-25 stabilizing RNA binding proteins (Kitamura et al., 2016). Multiple studies have concluded that mutant and wild type SOD1 aggregates can seed cytoplasmic inclusion bodies in healthy neurons (Münch et al., 2011; Polymenidou et al., 2011; Smethurst et al., 2016; Walker & Jucker 2015). TDP-43 aggregates have also displayed similar behivior of cell-to-cell propogation in vitro (Nonaka et al., 2013; Polymenidou et al., 2011; Walker & Jucker 2015; Wei, Yuanyuan et al., 2016). This suggests that both SOD1 and TDP-43 misfolded proteins seed aggregation and ALS propogtion that infects adjacent cells. However, the primary method of SOD1 and TDP-43 prion-like propgation has still not been fully elucidated.

Alzheimer’s disease (AD) is an irreversible, age-related neurodegenerative disorder clinically characterized by progressive loss of cognitive functions and behavioral disturbances. AD is associated with widespread accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles that disrupt the homeostatic processes in the brain and result in severe cognitive deterioration. Although the exact cause of AD is still unknown but preclinical studies have emphasized that deficits in the functioning of the ubiquitin-proteasome system (UPS) is the major underlying factor for abnormal accumulation of Aβ, and associated cognitive alterations. (PMID: - 24512022) To date, there are no effective disease-modifying therapies for AD and existing drugs