Mitochondrial dysfunctional activity and the relationship with parkinson(2)


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Mitochondrial dysfunctional activity and the relationship with parkinson(2)

  1. 1. Mitochondrial Dysfunctional Activity and the relationship with Parkinson’s disease.<br />Carlos Santos-Pérez<br />Department of Biology, University of Puerto Rico, Cayey Puerto Rico<br />Abstract<br />Introduction<br />Parkinson Disease is the second most common neurodegenerative disorder after the Alzheimer Disease. The sings and symptoms of this disease can be stiffness of the muscle, trembling and also difficulty in swallowing, speaking and chewing. It’s known that it is cause by the absence of dopaminergic neurons. For that reason the brain doesn’t have the enough neurotransmitter, that it’s called dopamine, to maintain a regulation of the Motor System. This disease can affect at least 4 million people in the United States of America each year. On the other hand the origin of the Parkinson Disease and the death of the dopaminergic neurons are unknown. Some of the fact that can represent a presage to find why this disease is affecting so many people is the relationship with Mitochondrial Dysfunction. In addition there is a possible relation between Mitochondrial Dysfunctional Activity and Programmed Cell Death or Apoptosis. <br />Mithocondrial Activity is characterized by the metabolism activity that implicate energy production in the cell but it have to be known that mitochondria contain its own DNA. This DNA can encode 13 proteins that are involved in phosphorylation reactions and 22 tRNA that are involve in the process of Cellular Respiration (Shults 2004). The Mitochondrial Activity doesn’t represent only a process that is reserved for the mitochondria because it’s also know that dysfunctional activity of the mitochondria can affect the Calcium and Potassium Channels (that are related with the synaptic activity between the neurons) and debacle the process that are related with the calcium production in the Endoplasmic Reticulum. It is also known that imbalance in the Redox reaction can propitiate the apoptotic activity in Dopaminergic Neurons. <br />Mitochondrial Apoptosis Activity and p53<br />Apoptosis is defined by the regulation of the death activity of the cells. This process allows the cells to disappear without expulsing harmful substances that can affect other cells. It is also important to know that apoptotic activity it’s affect normally to unnecessary cells, old cells and unhealthy cells (cells that are invaded by a virus). The mitochondria have a principal role in the apoptotic activity of the cells. Accumulated evidence has shown that an irregular apoptotic activity can represent an excess death activity of dopaminergic neurons (Andersen 2001). There are two possible pathways that can be a signal for apoptotic activity: external and internal (Reed 2002). There are some proapoptotic factors that are involve in both of the pathways. For example when a cell suffer of tumorgenesis or the cell cycle is abnormal the mitochondria release the proapoptotic factor name cytochrome c, consequently this activate the caspases pathways and the inhibition of the protein caspases. (Shapira and Orth 2001) There are other apoptotic factors such as a flavoproteinname Apoptotic-inducin factor 1 that is involve with the nuclease and nuclease activators. This flavoprotein synthesis is supposed to be genetically controlled. Also another proapoptotic factors are the members of the Bcl-2 family of protein (Shultz 2004). This protein family has a close relationship to a tumor suppressant named p53. This p53 protein can mutate and can mediate in a disrigulation of the Bcl-2 family of protein in the mitochondria. This can cause an apoptosis that it’s not necessary at the moment. That’s what happens in some of the Parkinson’s disease patients. To prove this relation between the apoptosis, mithocondrial activity and the expression of the p53 protein there are some researches that are based in post-mortem, in vitro and in vivo subjects. In the pos-mortem tissues with Parkinson Disease that was evaluated by Monte et al in 1998 there was an increase of p53 expression of the patient dopaminergic cells. Also the expression of phospho 38 increase causing a disrigulation in the MAPK pathway (responsible of phosphorilation) and for that reason a excessive production of mutated p53. <br />In the case of in vitro and in vivo models of Parkinson Disease, the researchers uses 1-methyl-4phenyl-1,2,3,6-tetrachydropyridine (MPTP), Rotenone and also 6-hydroxydopamine that are mediators to abrogate for dysfunctional activity in the Complex I of the mitochondria to cause and induce Parkinson Disease to animal and for in vitro cases.(Blum et al 2001) This model represent a very strong relation between the expression of a mutated p53 form and the toxins that abrogate for the dopaminergic cell damage. So basically it can be establish that it’s like a linear reaction. There is damage because the Parkinson Disease profactors in the Complex I of the mitochondria, this cause and increase in the p53 mutate form and this can lead to unnecessary apopototic activity in the dopaminergic neuron of the nigral substancia. (Blum et al 2001) <br />Decreasing of the Complex I Activity and Cellular Respiration<br />There is a very close relation between the reduction of the complex I of the mitochondria and the neurotoxin that presage the irregular synaptic process between the dopaminergic cells. Winkfholer and Haas in 2009 confirmed what Schapira et al 1990 established. They studied selected regions in the brain and also researched tissues that was from Advanced Pakinson Disease Patients. His studies are relevant because they found a significant reduction in activity of the complex I in the mitochondria. This researchers also reason about that the medication of the Parkinso Disease Patients may be are provoking the deregulated behavior of the mitochondria. That’s why Haas and Shults in 2004 design a methodology that involves some variables that Schapira’s research didn’t evaluate. They evaluate and compared untreated and early PD, age and gender matches control. The results of this research was that early and untreated patients have a Dysfunctional Mithocondrial activity specially in the Comples I and III.(Shults 2004).<br />On the other hand the cause of this is related with MPTP. This neurotoxin is metabolized by mitochondrial monoamine oxidase (Chiba et al 1984; Barnajee et al 2008) This neurotoxin accumulates in the mitochondrial and quickly affect the electron transport chain of the Cellular Respiration. <br />Endoplasmic Reticulum and Mitochondrial Dysfunctional Activity<br />Parkinson Disease, a progressive neurodegenerative disease, can be related with the Endoplasmic Reticulum Stress and dysfunction of the mitochondria in the dopaminergic neurotransmission cells. The researches establish this hypothesis: the calcium is the mediator between the Endoplasmic Reticulum and the Mitochondria crosstalk causing a series of signal that is traduce by the cell in apoptosis (Cell Death). To prove this they use two principal methods: the first is to indentify how much NADH is synthesizes by the mitochondria during the Cellular Respiration and the second is a fluorometric measurement of ER and Mitochondria Calcium levels. The results of this research were that the hypothesis was true. They found that when MPP+ (neurotoxin) increase, the activity or the mitochondria decrease causing the apoptosis. Also they discovered a wide relation between the calcium and the mitochondria apoptotic activity. (Moniz et al 2009)<br /> <br />Deletion of mitochondrial DNA agents that can induce PD<br />Mitochondrial 4977b deletion had proven to be related with the Parkinson Disease and the movement disorders cause by the neurological system but there is a conflict between what caused the deletion of this mtDNA: the aging or the PD itself. The researches are trying to prove that the deletion of this mtDNA is caused by the nigral neurons of the patients that have PD. The process or methodology that they were using was the use of insidious hybridization assay. The have a population of 47 PD patients. Finally they found that the PD was not related with the Mitochondrial 4977b deletion. Furthermore, the aging in conjunction with the PD was not the cause of the Deletion. They conclude that maybe the deletion it’s not directly related with the PD. On the other hand they expressed that if this is right then it have to be that the mutations are affecting the complexes of the mitochondria and this is affecting the apoptotic activity of this neurotransmission cells. (Zhang et al 2002). <br />