Essay: Neurodegenerative diseases

Neurodegenerative diseases impose a burden in the most part of the society and the mechanism underlying neuronal dysfunction and degeneration (Dimitriadi and Hart, 2010). The neuron degeneration is the process in which the neurons are progressively loss there functions and structure that include the death of the neurons. Amyotrophic lateral sclerosis, Parkinson’s, Alzheimer’s and Huntington’s are the Neurodegenerative diseases those occur as a result of neurodegenerative processes. These types of neurodegenerative diseases are incurable, resulting in progressive degeneration or death of neuron cells. Neuron degeneration can be found in several levels of neuronal circuit ranging from molecular to systemic.
As the longevity increases, neurodegenerative diseases become more problematic and prevalent specifically as treatments for these disorders are unavailable or ineffective. Alzheimer’s disease is the most commonplace and prevalent neurodegenerative disorder characterized by a degeneration of neurons. This neurodegenerative diseases attacks to the nerve cells in all part of the cortex of the brain therefore causes impairment in a person’s abilities to govern the emotions, identify the errors and patterns (Nytimes.com).
Alzheimer’s disease named because it can be first described by Alzheimer Alois in 1907. The Alzheimer’s is the neurodegenerative disease that can be characterized by the presence of senile plaques and neurofibrillary tangles in the brain of the individuals who is affected by this disease. The accumulation and aggregation of βA in the brain this causes the neurodegenerative disease called Alzheimer’s disease is the most frequent neurodegenerative disorder and this also a most common cause of dementia in the elderly (Palop and Mucke, 2010).
For the molecular conservation in neuronal signaling pathways in invertebrate and vertebrate species, the researchers have interest to do research with the nematode C.elegans to identify the mechanism of neurodegenerative disorders. C.elegans has neurotransmitters and associated receptors those are found in higher eukaryotes. This includes dopamine, acetylcholine, Gama-amino butyric acid (GABA), and serotonin (Boyd et al., 2010).
The C.elegans also used to express proteins which are associated with neurodegenerative disease related genes. The C.elegans is one of the most thoroughly studying model organisms in terms of its genetics, cell biology, development and behavior (Boyd et al., 2010). Model organism C.elegans is useful to do research in the field of biomedical and in the molecular determinants of human disease and it also provide the information to develop the new therapeutic inventions against the human diseases (Markaki and Tavernaraskis, 2010). This model organism is a powerful organism to study the molecular and the cellular aspects of human disease in vivo (Markaki and Tavernaraskis, 2010). The nematode C.elegans used as an important model organism in various fields including neurobiology, developmental biology and genetics (Leung et al., 2008). C.elegans was originally chosen in 1963 by Sydney Brenner as a model organism to study the genetics of development and the nervous system (Palop and Mucke, 2010). Over the last three decades the C.elegans gains popularity in toxicological research as a model organism (McVey KA., 2012).
C.elegans has number of properties due to which it is use as model organism:
• The C.elegans is a free living soil nematode roundworm with small body size of ~1 mm in length with a short generation cycle of ~3 days and has ~3 weeks of lifespan (Brenner S., 1974).
• C.elegans has transparent body that allows visualization and monitored the internal development of all cells and organs (Boyd et al., 2010).
• The culture and maintenance of the C.elegans is an inexpensive and it is easy to culture in the laboratory.
• The neuron degeneration and protein inclusions are easy to detect and quantify by using the techniques.
• The adult C.elegans hermaphrodite and male both are contains different numbers neurons in the nervous system. The hermaphrodite contains 302 neuron and thus position and identity remain store from animal to animal (White et al., 1986), in that the 282 neurons in the somatic nervous system and 20 neurons in the pharyngeal nervous system (White et al., 1986). These nervous system controls the feeding, locomotion, defecation, reproduction and environmental sensing (Boyd et al., 2010) and the male contains the 473 neurons (Emmons SW. 2005).
• C.elegans conserved the major neurotransmitter system which allows the study for the neuroscientists (Dimitriadi and Hart, 2010)
• 42% genes those are related to human disease are ortholog of C.elegans (Culetto and Sattelle, 2000).
• C.elegans reproduces quickly in large numbers (Boyd et al., 2012). The single hermaphrodite has ability to produce ~300 offspring those mature at four larval stages of L1-L4 (Markaki and Tavernarakis, 2010).
Systematics of C.elegans
Kingdom : Animalia
Phylum : Nematode
Class : Chromadorea
Order : Rhabditida
Family : Rhabditidae
Genus : Caenorhabditis
Species : elegans
Binomial classification: Caenorhabditis elegans (Maupas, 1900).
The C.elegans has a powerful animal model to study the molecular and cellular aspects of human diseases in vivo. C. elegans model of neuronal dysfunction have been established for a number of neurodegenerative diseases, including AD, PD and polyglutamine-expansion disorders. The model organism C.elegans is useful model to express human proteins those are associated with neuron degeneration or neurodegenerative diseases (Dimitriadi and Hart, 2010). C.elegans is a model that has successfully employed for the investigation of neurological effects and the pesticides induced toxicity (Vinuela et al., 2010). In C.elegans, acetylcholine is the major neurotransmitter which directly or indirectly regulates egg laying (Bany et al., 2003) and locomotion (Mullen et al., 2007).
Neuron degeneration or neurodegenerative diseases may be caused by various ways as due to the mutation in the gene that directs the production of enzymes like aspartoacylase (ASPA) this allows the buildup of N-acetyl aspartic acid (NAA) in the brain this causes the damage of the myelin that provide the protective coating to the nerve fiber in the brain that ensure that nerve impulses are properly transmitted in the brain because it causes the effect on the growth of the myelin sheath it effect the transmission of neurons in the brain, the aggregation in the microtubule associated proteins tau causes the neurodegeneration in the brain (Palop and Mucke, 2010), loss of glutamate transporter EAAT2 (excitatory amino acid transporter 2) protein in motor cortex and spinal cord, glutamate mediated excitotoxicity of nitric oxide synthesis containing neurons results the Paraquat induced neurotoxicity (Uversky N.V., 2004). Pesticides may also be one of the reasons for the degeneration of the neurons. Earlier studies shows that the pesticides like Rotenone, Carbamates are the known pesticides those are causing neurodegenerative diseases like Huntington’s, Alzheimer’s and dementia respectively (Population health branch, 2002).
In the present study, we are going to check the effect of some other pesticides those are commonly used to control insects or pests in commercially available product such as Mortien, All out, Mosquito coil, Raid, Baygon and these pesticides are also used in the agriculture to control pests. So here we are going to check the effect of these pesticides on the behavioral, developmental and neurodegenerative level using C.elegans as model organism. As behavior of an organism is the cumulative interaction of various factors and after the environmental exposures the assessment of behavioral and developmental changes can serve as a sensitive indicator of adverse effect. As behavioral and developmental changes alteration may be due to the direct effect on nervous system.
Pesticides those are extensively and intensively used in the agriculture caused the environmental pollution (Alhewairinin et al., 2016). Pesticides are substances for attracting, seducing and destroying the pest (US Environmental 2007). In India 234 registered pesticides used out of these four pesticides are WHO class 1a pesticide, 15 are WHO class 1b pesticides, and 76 are WHO class 2nd pesticides together constituting 40% of the registered pesticides in India (India For Safe Food.htm).
TABLE: 1 List of selected pesticides and their classes
Class Pesticides
Carbamate Propoxur
Organophosphate Chlorpyrifos
Pyrethroid Allethrin, Resmethrin, Prallethrin, Cyfluthrin, Bifenthrin, Transfluthrin
Botanical insecticide Pyrethrum
Selected pesticides for the present study mainly belongs to four classes are carbamates, pyrethroids, organophosphates, and botanical insecticides (Table 1). Pesticides are powerful agent that kills unwanted insects in the applied area (Schock et al., 2012). Classification of pesticides with chemical properties and functionality is available on several informative website (www.epa.gov/pesticides/about/types.htm and http://www.alanwood.net/pesticides).
Carbamate pesticides cause the inhibition of Acetylcholine. Acetylcholine was first discovered in the 1920s the first known neurotransmitter and the role of Acetylcholine found in the brain. Acetylcholine plays a role in learning and memory (Deep Dive Admin, 2015). Alzheimer’s is the disease caused due to the loss of acetylcholinestrase from the brain an enzyme important for the transmission of nerve impulses. The mechanism of carbamates poisoning, except the herbicidal carbamates, involves the inactivation of active site of acetylcholinestrase this causes the accumulation of acetylcholine and acetylcholinestrase is the enzyme important for the transmission of nerve impulses. When this enzyme is inhibited this results acetylcholine accumulation and the cholinergic toxicity result due to the continuous stimulation of cholinergic receptors throughout the central and peripheral nervous systems United States Environment Protection Agency (USEPA, 2007).
TABLE: 2 List of pesticides used in the insect repellent:
Commercially available products Pesticides
Baygon Cyfluthrin, Transfluthrin, Prallethrin, Propoxur, Chlorpyrifos
All out Transfluthrin
Mortein coil Allethrin, Resmethrin
Raid Cyfluthrin, Allethrin
Capture Bifenthrin
Scourge Resmethrin
Dursban Chlorpyrifos
Lorsban Chlorpyrifos
Rusban Chlorpyrifos
Propoxur is a Carbamate pesticide widely used in agriculture and public health programs (Mohamadin et al., 2010). Propoxur commonly sold under the trade name Baygon and Bayer AG was first registered Propoxur in 1963. Propoxur is used to control ticks, fleas, and a variety of insects including crickets, ants, wasps, cockroaches and silverfish (Propoxur, 2011).
Organophosphates pesticides is widely used in the agriculture to increase the agricultural yields by the killing of pest but the continued use of organophosphates also present a threat to human and also in the environmental health and they are applied to food crops and in household environments to control the insects pest (Yen, 2012). Exposure of organophosphates affects the nervous system by the accumulation of acetylcholine which results the inhibition of acetylcholinestrase therefore the use of organophosphates increases the risk to develop Alzheimer’s disease in exposed population (Yadav et al., 2016). The chlorpyrifos is applied for the control of cockroaches, flea, termites and mosquitoes. This may affect the central nervous system and the exposure of chlorpyrifos is cause vomiting, nausea, headache, muscle twitching and unconsciousness (Beyond pesticides, 2000).
Pyrethroids are the pesticides those used to kill insects, including mosquitoes. Pyrethroids are used in many commercially available products those are also used to control mosquitoes. The professionals apply pyrethroids as an ultra low volume (ULV) spray. Ultra low volume sprayers release tiny aerosol droplets and these droplets stay in the air and kill the adult mosquitoes on contact. Pyrethroids are approved by U.S. Environment Protection Agency (USEPA) for control of adult mosquito (Pyrethroid insecticides.htm). Allethrin, Resmethrin, cyfluthrin, transfluthrin, prallethrin, and Bifenthrin are the pesticides used in the class of pyrethroids available in commercially available products. The exposure of the Allethrin causes the insects to become paralyzed before dying. Allethrin is firstly introduced in 1949 and synthesized by the Milton S, Schechter in the United States (Pesticide information profile, 1993). This pesticide is used to control adult mosquitoes and flying insects in home, greenhouse and industrial sites and the transfluthrin is issued to use in the indoor environment against flies, mosquitoes and cockroaches.
The botanical insecticide includes the pyrethrum. The purified form of pyrethrum is known as pyrethrin. The term pyrethrum refers to the dried and powder form of flower heads of a white flower plant belonging to the genus chrysanthemum. The six esters collectively known as pyrethrin, found within the pyrethrum extract (Duchon et al., 2009). Pyrethroids are pesticides those are used to kill insects and pest including mosquitoes by the mix pyrethroids with water or oil and apply to kills the flying adult (Rauner, 2007). The pyrethroid pesticides are the neurotoxin pesticides those are able to inhibit the transfer of the nerve impulses by blocking the nicotinic acetylcholine receptors (Krzepilko and Swiecilo, 2007).
This work has led to know us about the neurotoxic effect of pesticides leading to neurodegenerative diseases in human. Humans may expose to pesticides through various routes, such as air, soil and water. When the pesticides applied directly on the target pest the whole site gets affected, including the crop plants, soil organisms and also humans and wildlife in the area. The pesticides used different way for the exposure; in air the respirable particles, respirable aerosols during spraying and vapors. Through soil the route is hand to mouth behavior, crawling on the ground and dermal contact. Children exposed when they are around the spraying area. The another route of exposure is water and food, through drinking water the persons can be affected and when the crops sprayed, fruits, vegetables, grains, fish, meat, eggs, dairy are the exposure source for the pesticides. The pesticides can cross the epithelium of the skin and mucous membranes that capable to exchange gases or nutrients. Respiratory absorption is high when the respiration is rapid at the time of playing and running. This study highlights that how this versatile organism C.elegans has used to model the aspect of human neuron degeneration and also contribute to our understanding of human neurodegenerative diseases caused due to the effect of pesticides those are available in the commercially available products as well as these are used in agriculture practices to control pests and we are getting exposed to these pesticides either to direct or indirect methods. (Dimitriadi and Hart, 2010).