Assignment: Essay
Option 2: Discussion on the potential role of acidic nano-particles in treatment of lysosome-related neurodegeneration
Lysosome has been recognised to be essential organelles that have waste removal function inside a cell and are involves in the digestion. There is also evidence that lysosomes have been linked to different neurodegenerative diseases.
The dysfunctional lysosomes caused degradation of protein and deposition of abnormal proteins that is one of the grounds towards neurogeneration as the person grows (i.e. related to age) (Zhang et al., 2009).
The impairment of lysosome organelles leads to lysosomal storage disorders. In addition, these organelles impairment also leads to quite a few neurodegenerative disorders by getting involved in the pathogenesis of diseases like amyotrophic lateral sclerosis, Parkinson disease, Alzheimer diseases, Niemann–Pick disease type C and Huntington disease.
In recent years, the focus is on the acidic nano-particles for lysosomal storage disorders and for their management of neurodegenerative diseases caused due to impaired lysosomal function. Lysosome shows the pathogenic conditions on different neurodegenerative diseases.
Abnormal protein degradation and deposition are possible because of the lysosomal dysfunction that may cause age-related neurodegeneration.
There have been evidences and clinical relevance for the treatment modalities towards nano-technologies, approaches of drug carrier, cell and gene therapies and others.
The purpose of the essay is to present a discussion on the potential role of acidic nano-particles towards the treatment of lysosome-related neurodegeneration. Nanoparticles are particles between 1 and 100 nanometres (nm) in size that have an interfacial layer.
It is made of nanoscale matter that has a significant infleucne on the properties. It includes ions, inorganic and organic molecules. In these particles, organic layer coats the inorganic layer and known as the stabilizers or passivating agents. In nanotechnology, a particle is defined as a small object that works as an entire unit in perspectives of properties.
It is a nano-object that works as the scientific interest for the medicinal treatments. It can also be significant for the treatment of lysosome-related neurodegeneration (Platt et al., 2012). These particles are small enough to confine their electrons and generate the quantum effects.
Lysosomal enzymes function generally in acidic surroundings in the body as it is necessary to be an acidic environment for the functioning of these enzymes. Increase of lysosomal pH can hinder their capacity to degrade material delivered to lysosomes through autophagy or phagocytosis.
The change in the abnormal lysosomal pH is a big reason behind diseases of accumulation. So, restoration of lysosomal pH can be effective for the improvement in cell function.
The propensity of nanoparticles to end up in the lysosome is significant to deliver the drugs to lysosomes. So, acidic nanoparticles can play an important role in generating acdici environment surrounding the lysosomes that can be helpful to lower lysosomal pH and enhance lysosomal degradation by the cultured human retinal pigmented epithelial cell line ARPE-19.
Acidic nanoparticles are made of poly (DL-lactide-co-glycolide) (PLGA) 502 H, PLGA 503 H and poly (DL-lactide) (PLA) that can be transferred to lysosomes of ARPE-19 cells within 60 min. PLGA 503 H and PLA play an important role in lowering lysosomal pH in cells.
PLA enhances binding of Bodipy-pepstatin-A to the active site of cathepsin D in degraded cells. So, this study will analyze the role of acid nanoparticles to lower lysosomal pH and improve degradative activity.
Potential role of acidic nano-particles
Nanoparticles are known for their non-toxic nature owing to which they are appealing towards the drug and gene delivery. They are made from the biodegradable polymers and have known to internalize into cells (in neurons) that belong to a mammal.
The United States Food and Drug Administration had approved nano-particles for lysosomes. One of the nano-particles is acidic nano-particles (aNP) of poly (DL-lactide-co-glycolide) PLGA for acting on the lysosomal pH and as passages to lysosomes.
Thus, the potential role of acidic nano-particles is towards its ability to acidify the impaired or sick lysosomes and to restore them for their lysosomal function i.e. autophagy to transport the cytoplasmic constituents and their degradation and recycling process.
It can be said that the key potential role as mentioned earlier of the nano-particles is its function to re-establish acidification defects of lysosomal. The treatment of PLGA acidic nano-particles is to undertake the re-acidification of the impaired or defective lysosomes which can have positive implication for variety of neurodegeneration diseases.
On the other hand, in pathological situations the role of acidic nanoparticles is yet to be determined fully (Platt et al., 2012). At the same time, it is revealed in the research of Bourdenx et al. (2016) that poly (DL-lactide-co-glycolide) (PLGA) acidic nano-particles (aNP) have been able to re-establish the function of impaired lysosomal in depleted cells.
The research used a sequence of toxin and genetic cellular models (ATP13A2-mutant) of Parkinson disease i.e. ATP13A2-mutant, glucocerebrosidase (GBA)-mutant cells, and genetic model of lysosomal-related myopathy whose function was restored by PLGA acidic nano-particles (Bourdenx et al., 2016).
Thus, from this research the potential role of PLGA-aNP was identified to be acting as a transport to the lysosome organelles within a period of twenty four hours and also to act on the lysosomal pH and to lower it to develop an acidic environment. The role of acidic nano-particles was also to set free the Chloroquine that slowdowns the autophagic flux and induces toxicity.
In relation to this, it can be said that the potential role of acidic nano-particles is to control the Lysosomal pH in treatment of lysosome-related neurodegeneration. The lysosome-related neurodegeneration diseases or disorder are regarded to have high deposit of abnormal (misfolded) proteins along with the degeneration of the neurons in the specific regions of the brain.
It is also characterised by increase in lysosomal pH causing impairment of these digestive organelle. Here, the role of acidic nano-particles comes into play as a new non-technology strategy due to their ability to restore the lysosomal function for treatment of pathogenic position in the neurodegeneration diseases.
In support of this, the study of Prévot et al. (2018) highlighted the role of PLGA Nanoemulsion to free the impaired lysosomes and also liberate the lysosomal pH in the genetic cellular framework of a neurodegeneration disease, Parkinson’s. On injecting the mouse brain with the nano-emulsion (red emitting dye), there was diffusion up to 500 µm where the nano-emulsion loaded with PLGA was able to internalise into the brain cells in the lysosomal compartment (Prévot et al., 2018).
Thus, it can be added that the role of nano-particles is and drug delivery mechanism to brain to potentially helpful in rescuing the lysosomal deficits in the context of pathological.
Another possible role of nano-particles can be towards the release of required lysosomal digestive enzymes to the target regions. The nano-particles can act as nano-carriers this will help in the release of therapeutic agents and increase their bioavailability so that cells can be protected from degradation.
In addition, the nano-particles will be useful as nano-carriers as there circulation time can be controlled as well as their rate of release so that an effective targeting of region in the body can be achieved for lysosome-related neurodegeneration diseases.
The nano-particles can be used to improve the therapeutic outcomes of the neurodegeneration diseases. It is found that the size of nano-particles carriers can range from 100–300 nm this is because these sizes are considered to be sufficient for the avoidance of passive diffusion via tissues (Ma et al., 2011) and also these sizes are adequate for transport mechanism in physiological context (Muro, 2010).
It can be said that nano-particles carriers can be used to target the cell-surface receptors for lysosomal transport as these receptors are engaged in endo-cytic way that leads to transfer across the cell for brain penetration to reach the specific regions.
From the discussion, it can be concluded that that nano-particles have significant potential with regards to the acidic nano-particles for the treatment of lysosome-related neurodegeneration diseases or disorders. The possible role is in relation to the mechanism of delivery of drug, transfer of lysosomes, action on the lysosomal pH to control it from increasing further and thus, lower the lysosomal pH.
It can also be summarized that aciic nano-particles are effective to reduce the pH level for lysosomes that enhances the functioning of its enzymes playing an important role in preventing the degrading activities. It can also be colocalized to the Lysosomal site as soon as possible that is crucial for instant actions to prevent the degradation process.
There is also restoration of the lysosomal function and acidification of the defective, impaired or sick lysosomes under its role. It also has possible role as a nano-particles carrier to release the lysosomal enzymes and targeting of specific regions in the brain for the release of therapeutic agents and lysosomal transport.
Option 2: Discussion on the role of mitochondrial dysfunction in age related neurodegenerative disease.
There are evidences from clinical studies that link the mitochondrial dysfunctions to be accountable for age –related neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS).
The mitochondrial mutation and nuclear DNA mutations (mitochondrial DNA (mtDNA) mutations) and environmental causes are the main reasons for mitochondrial dysfunctions.
The deficiency in mitochondrial metabolism, the damage to the mitochondrial structure (increased fragmentation and decreased fusion), and loss of mitochondrial functions (such as ATP production) and the electron transport chain defect are considered to be involved in the pathogenesis of neurodegenerative diseases, in particular, Alzheimer’s disease (Exner et al., 2012).
The dysfunction mitochondria are unable to produce sufficient adenosine triphosphate (ATP) which leads to unhealthy neuron. The purpose of the essay is to present a discussion on the role of mitochondrial dysfunction with regards to the age related neurodegenerative diseases.
Role of mitochondrial dysfunction
The mitochondrial dysfunctions are known to be responsible for the causing negative effect on functions of neurons and also neuronal structure as the functional effect and structure changes commonly found to occur in a number of neurodegenerative diseases (Johri and Beal, 2012).
The cellular mechanism has a close resemblance with the mitochondria therefore; the dysfunctions in mitochondria are the involved in the pathogenesis of age related neurodegenerative diseases.
There are deletions in mitochondrial DNA and mutations due to incorrect mitochondrial fusion. When there fusion is not adequate it of the mitochondrial constituents and the membrane (lipid), then it will not undertake its mitochondrial DNA repair activity.
This will also lead to accumulation of mitochondria that is non-functional in nature and there would be an unequal distribution of the mitochondrial metabolites. Thus, it can be discussed that the role of mitochondrial dysfunction is associated with neurodegenerative diseases pathogenesis.
In the context of Alzheimer’s disease, it can be also discussed that mitochondrial dysfunction play a major role in pathogenesis of this neurodegenerative diseases.
It can be conferred that atypical mitochondrial enzyme activities reduced the level of dehydrogenase (α-keto and private) as well as cytochrome oxidase activity with age affecting neurons cells (Johri and Beal, 2012).
Other than this, it reduces the production level of ATP and increase the level of free radical production. In the course of pathological and physiological episodes, there is formation of free radicals where activation of enzymes and regulation of cell cycle require reactive oxygen species.
The increase of free radicals presence damages the protein and lipid (Lane et al., 2015). The dysfunction also plays a part to damage the protein and DNA and affect the viability of the cells in brain due to defect in function of mitochondria.
In age related neurodegenerative diseases, there is also defect in the mitochondrial DNA due to its mitochondrial dysfunction which leads to changes in the DNA because of mtDNA accumulation and the mutant proteins accumulation further affecting the structure and function of neurons and death of brain cells.
The mitochondrial gene expressions also become abnormal in the brain which also impairs the metabolism of the mitochondria affecting their responses to mutant APP and Aβ. Also from the above discussion, it can be pointed that the structure of mitochondrial changes in the neurons in the brain tissue due to its fragmentation.
In the development of Alzheimer’s disease the role of mitochondrial dysfunction is prominent where the synaptic activities are interfered by the synaptic mitochondria by ATP production at synapse, release of neurotransmitters and liberating the synaptic vessels (Reddy, 2009).
Thus, the mitochondrial dysfunction takes part to disrupt the communication across neurons to affect the memory and cognitive functions and also leads to low ATP production and supply.
The mitochondrial dysfunction play a part in affecting the mitochondrial movements and making them abnormal because of inactive mitochondria and this also points to the case of unhealthy neurons.
The mitochondrial dysfunction leads to abnormalities which causes alterations in the mitochondrial DNA (mtDNA (Johri and Beal, 2012), enhance the mitochondrial fragmentation, unusual mitochondrial gene expressions and reduced mitochondrial enzyme activities and mitochondrial fusion (Reddy, 2009).
It can be discussed that the when the mutant APP and Aβ linked mitochondria are dysfunctional they are not able to establish their movement from the cell body towards the synapses thus, are not able to supply the energy currencies (ATP) to the nerve terminals.
This is because of the entry of mutant APP and Aβ in the mitochondria that hinder the movement of mitochondrial proteins (nuclear-encoded) and bring the free radicals that cause oxidative damage to cells and their death. Thus, there is low level of ATP which leads to loss of synaptic, its degeneration and finally the death of neurons.
This leads to cognitive function impairment towards the development of early stages of neurodegenerative diseases. In essence, it can be discussed that mitochondrial dysfunction role can be related to the presence and accumulation of Aβ in the brain. The Aβ targets mitochondria leading to neurotoxicity to a certain extent.
Also, the oxidative stress highlights the role of mitochondrial dysfunction in pathogenesis of different neurodegenerative diseases in particularly, amyotrophic lateral sclerosis and Parkinson’s disease. The brain has high level of oxygen demand thus is highly susceptible to the risk of oxidative stress and also results in decline of the cognitive function with age.
The oxidative stress causes damage to the mitochondrial DNA bases which threatens the life of cells and the protons are brought from mitochondrial matrix to across the inner mitochondrial membrane in the electron transport chain while the stress also alters the level of Aβ (Exner et al., 2012).
In related context, it can be discussed that the role of mitochondrial dysfunction is also towards distressing the respiratory processes which also leads to death of neurons which is a feature of development of neurodegenerative diseases (Hawking, 2016).
When the electrons come across the inner mitochondrial membrane, the electrons can form superoxide radical when it relate with oxygen molecules. The superoxide radical is a reactive oxygen species. The mitochondria have a defence mechanism towards reactive oxygen species that can be formed at some point in the normal process of respiration (Lane et al., 2015).
In order to protect the damage to cells, protein and lipid the stability of oxidant and anti-oxidant is required. On the other hand, this stability is affected due to mitochondrial abnormality and dysfunction.
In addition, mitochondrial dysfunction hampers this defence mechanism thus; results in increase of reactive oxygen species as they are not destroyed by mitochondria. There is also insufficiency of enzyme for reducing the oxygen radicals in the mitochondrial respiratory chain.
The key enzyme accountable is cytochrome c oxidase (COX) which is in deficit during mitochondrial dysfunction. Thus, there are bio-chemical changes due to free radicals and cause lipid peroxidation (Hawking, 2016) which damages the cells which is one of the characteristic feature in neurodegenerative disease.
In the context of mitochondrial dysfunction in Parkinson disease, it can be discussed that the mitochondrial dynamic play an important role in the mechanism of this neurodegenerative disease as the mutations occur which results in an atypical episode of mitochondrial fission.
The mytochondrial dysfunction failure to form defence mechanism that bring about the development of oxidized α-synuclein in the direction of cause of oxidative stress. This stress further raises the presence of oxidized α-synuclein.
In the context of mitochondrial dysfunction in Amyotrophic lateral sclerosis, it can be discussed that mitochondrial dysfunction play a part in the deterioration of the brain stem and neurons which is progressive with age.
This is due to abnormal changes in the morphology of mitochondria and leading to alteration in the mitochondrial fission and fusion regulators. It is also reported that there is unusual mitochondrial fragmentation and mutations in the cells of persons with ALS (Lane et al., 2015).
It can be conferred that the mitochondrial mutations character seems to be associated with the age related neurodegenerative diseases in their mechanism of development. The mitochondrial mutations increase the level of mitochondria that are mutant and non-functional.
Due to this, there is affect on the production of adenosine triphosphate making it unproductive as there is lower production of ATP. Here, the episode of mitochondrial dysfunction is detected.
There is an change in mitochondrial morphology and dynamics with an increase in the production of free radicals/ reactive oxygen species and damage to the mitochondrial enzymatic.
These changes disrupt the process of mitochondrial fission and fusion making it unusual and lower the transfer of mitochondria/ ATP to axons (nerve terminals) and thus, the functions of mitochondrial action are affected and the degeneration of cells are progressive with age towards the development of early stages of neurodegenerative diseases.
Based on above points, it can be concluded that the role of mitochondrial dysfunction in the mechanism and pathogenesis in the different neurodegenerative diseases has been uncovered to a certain extent. There role in abnormal mitochondrial fission and fusion and the effect on the oxidative stress that hampers the neuronal function.
It can be concluded that there are several evidence that suggest the major role of mitochondrial dysfunction to be involved in age-related neurodegenerative diseases due to structural and functional changes from accumulation of mutant protein and mtDNA. It also has a role in the oxidative stress and to reduce the respiratory processes causing neuronal deaths.
Bourdenx, M., Daniel, J., Genin, E., Soria, F.N., Blanchard-Desce, M., Bezard, E. and Dehay, B., 2016. Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases. Autophagy, 12(3), pp.472-483.
Exner, N., Lutz, A.K., Haass, C. and Winklhofer, K.F., 2012. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. The EMBO journal, 31(14), pp.3038-3062.
Hawking, Z.L., 2016. Alzheimer’s disease: the role of mitochondrial dysfunction and potential new therapies. Bioscience Horizons: The International Journal of Student Research, 9.
Johri, A. and Beal, M.F., 2012. Mitochondrial dysfunction in neurodegenerative diseases. Journal of Pharmacology and Experimental Therapeutics, 342(3), pp.619-630.
Lane, R.K., Hilsabeck, T. and Rea, S.L., 2015. The role of mitochondrial dysfunction in age-related diseases. Biochimica et Biophysica Acta (BBA)-Bioenergetics, 1847(11), pp.1387-1400.
Ma, X., Wu, Y., Jin, S., Tian, Y., Zhang, X., Zhao, Y., Yu, L. and Liang, X.J., 2011. Gold nanoparticles induce autophagosome accumulation through size-dependent nanoparticle uptake and lysosome impairment. ACS nano, 5(11), pp.8629-8639.
Muro, S., 2010. New biotechnological and nanomedicine strategies for treatment of lysosomal storage disorders. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 2(2), pp.189-204.
Platt, F.M., Boland, B. and van der Spoel, A.C., 2012. Lysosomal storage disorders: The cellular impact of lysosomal dysfunction. J Cell Biol, 199(5), pp.723-734.
Prévot, G., Soria, F.N., Thiolat, M.L., Daniel, J., Verlhac, J.B., Blanchard-Desce, M., Bezard, E., Barthélémy, P., Crauste-Manciet, S. and Dehay, B., 2018. Harnessing Lysosomal pH through PLGA Nanoemulsion as a Treatment of Lysosomal-Related Neurodegenerative Diseases. Bioconjugate chemistry, 29(12), pp.4083-4089.
Reddy, P.H., 2009. Role of mitochondria in neurodegenerative diseases: mitochondria as a therapeutic target in Alzheimer’s disease. CNS spectrums, 14(S7), pp.8-13.
Zhang, L., Sheng, R. and Qin, Z., 2009. The lysosome and neurodegenerative diseases. Acta biochimica et biophysica Sinica, 41(6), pp.437-445.
