Parkinson's Disease Pathway
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Parkinson's Disease Pathway
Parkinsons disease is a Neurodegenerative disorder characterized by the progressive loss of Dopaminergic neurons in the substantia nigra and the appearance of intracellular inclusions, named Lewy bodies and Lewy neurites in the remaining nigral neurons. The Substantia nigra is located in the midbrain region of the brain. It consists of two parts: the SNc (pars compacta), and the SNr (pars reticulata). The pars compacta produces dopamine and is the part that degenerates in Parkinsons disease. It is the second most common form of neurodegenerative disease after Alzheimers, affecting about 1% of people over 65 years old and 4-5% of people over 85 years. Symptoms of Parkinsons disease include a resting tremor, rigidity, bradykinesia, gait dysfunction and postural instability. It is not known what actually initiates the development of Parkinsons disease; most likely it is a combination of inherited risk factors and environmental toxin exposure. Several genes and their corresponding protein products are known to be involved in Parkinsons disease. Proteins and genes associated with Parkinsons disease include Alpha-Synuclein, Parkin and UCHL1 (Ubiquitin Carboxy-terminal Hydrolase L1), PINK1 (PTEN Induced Kinase-1) and DJ1. The majority of Parkinsons disease is Sporadic, although there are rare genetic Familial forms of the disease. In Sporadic Parkinsons disease, oxidative stress (Glutathione depletion, Iron deposition, increased markers of lipid peroxidation, ROS (Reactive Oxygen Species), oxidative DNA damage, and protein oxidation) and mitochondrial dysfunction play prominent roles in the death of DA (Dopamine) neurons, perhaps through a combination of excitotoxic, necrotic, and apoptotic mechanisms. Three genes have been clearly linked to Familial Parkinsons disease, and a number of other genes or genetic linkages have been identified that may cause Parkinsons disease. Mutations in the Alpha-Synuclein, LRRK2 (Leucine-Rich Repeat Kinase-2) and UCHL1 (Ubiquitin C-terminal esterase L1) genes cause dominant forms of Familial PD. In contrast, mutations in Parkin, DJ1 and the newly identified PINK1 (PTEN-induced Kinase-1) are responsible for recessive forms of familial PD (Ref.1 & 2).

The first Parkinson’s disease gene to be identified, PARK1, was the gene encoding the presynaptic protein Alpha-Synuclein, which are inherited in an Autosomal dominant manner. Alpha-Synuclein is a presynaptic nerve terminal protein of 140 amino acid, which appears to be natively unfolded and represents about 1% of the cytosolic protein in the brain. Currently, Alpha-Synuclein is center stage, as the acquisition of new pathological function of Alpha-Synuclein seems to be important in both Familial and Sporadic Parkinsons disease. Alpha-Synuclein is believed to play an important role in killing cells by accumulation of toxic aggregates, inhibition of Proteasomal function, induction of apoptotic death machinery, autophagy and interference with cell survival pathways. Oxidative stress and heavy metal toxicity potentiates Alpha-Synuclein aggregation and toxicity. Soluble Alpha-Synuclein protein complexes that contain the anti-apoptotic 14-3-3 protein may render endogenous level of DA toxic through the generation of ROS (Reactive Oxygen Species). In Parkinsons disease, Alpha-Synuclein accumulates in the cell bodies and neurites of degenerating neurons as a major component of Lewy bodies and Lewy neuritis (Ref.3).

The second Parkinsons disease gene, PARK2, is caused by mutations in the gene for Parkin, and it leads to AR-JP (Autosomal Recessive Juvenile Parkinsonism). Along with Alpha-Synuclein, Parkin is also found in Lewy bodies and the Parkin protein is an E3 Ubiquitin Ligase. The Parkin gene has an estimated genomic size of 500 kb and consists of 12 coding exons with an open reading frame of 1395 bp. The corresponding protein, Parkin, is divided into three parts: the Amino-terminal Ubl domain, the Carboxy-terminal RING-box and the linker region, which connects the former two segments. The C-terminal RING-box region consists of three domains termed RING1, RING2 and IBR (for in-between-RING). Parkin appears to work in conjuction with UbA1 (Ubiquitin Activating-1), an E1 protein. It uses Ubc (Ubiquitin-Conjugating) enzymes, both UbCH7 and UbCH8 as its E2s, and it also utilizes the ER (Endoplasmic Reticulum)-associated E2s UbC6 and UbC7. The E1 delivers Ubiquitin to the E2 in a cycle that creates an increasing chain of Ubiquitin. The Parkin E3 ligates this onto substrates and so tags these proteins in normal cells, targeting them for destruction in the proteosome. Several substrates of Parkin have been identified. They include CDCRel1 Cell Division Cycle Related-1), PAELR (Parkin-Associated Endothelin-receptor-Like Receptor), Ataxin-3, Cyclin-E, Aminoacyl-tRNA Synthetase and Syt11 (Synaptotagmin-11) (Ref.1 & 4).

CDCRel1 is a member of the septin family comprising GTPases required for the completion of cytokinesis in diverse organisms. Members of the septin family of proteins may function in synaptic vesicle transport, fusion, or recycling events in the brain. CDCRel1 is predominantly expressed in the nervous system and is associated with membrane fractions. CDCRel1 directly binds to Syntaxin via the SNARE interaction domain and appears to be dispensable in neurotransmitter release. Parkin ubiquitinates and promotes the degradation of CDCRel1. Another substrate of Parkin is PAELR (Parkin-Associated Endothelin-receptor-Like receptor), a homolog of Endothelin Receptor type B, whose accumulation in brains with Parkin mutations apparently leads to unfolded protein stress in endoplasmic reticulum and may cause selective neuronal death. Parkin ubiquitinates PAELR and promotes the degradation of the insoluble form of the protein. Parkin is a novel Tubulin-binding protein, as well as a microtubule-associated protein. Its ability to enhance the ubiquitination and degradation of misfolded Tubulin may play a significant role in protecting neurons from toxins that cause PD. Parkin also interacts with, ubiquitylates and promotes the degradation of p38, a key structural component of the mammalian Aminoacyl-tRNA Synthetase complex, also known as EPRS. Thus, p38 plays a role in the pathogenesis of PD, opening the way for a detailed examination of its potential non-canonical role in neurodegeneration. Parkin also ubiquitinates both normal and mutant Ataxin-2, resulting in increased degradation. Synaptotagmin XI is another synaptic protein substrate for Parkin. Parkin also ubiquitinates and degrades Cyclin-E. More recently, two proteins related to Alpha-Synuclein, were found to be substrates of Parkin. One of them is an O-glycosylated form of Alpha-Synuclein; the other is the Alpha-Synuclein-binding protein, Synphilin-1. It was recently reported that Parkin interacts with the O-glycosylated form of Alpha-Synuclein, known as AlphaSp-22, but not with its intact form. Parkin directly ubiquitinates AlphaSp-22, which is abundantly accumulated in the brains of Parkin-deficient autosomal recessive Parkinsons disease patients, and the loss of Parkin function causes pathological accumulation of Alpha-Synuclein. The dynamic glycosylation of serine or threonine residues on nuclear and cytoplasmic proteins by O-GlcNAc is abundant in all multicellular eukaryotes. The diversity of proteins modified by O-GlcNAc implies its importance in many basic cellular and disease processes. Failure of Parkin-mediated degradation of Alpha-Synuclein may be a key factor leading to the death of dopaminergic neurons. Parkin is inactivated by Caspase cleavage. Cellular Parkin can be cleaved by Caspase1 and Caspase8. Because Parkin is a direct substrate of Caspase1 and Caspase8, Parkin cleavage might be important for the degeneration of dopaminergic neurons. Caspase1- and Caspase8-dependent Parkin cleavage in sporadic Parkinsons disease may play an important role in the degenerative process by initiating a vicious circle that leads to the accumulation of toxic Parkin substrates. The failure to remove these substrates may lead directly to cell death or lower the cellular threshold to further stressful insults (Ref.5, 6 & 7).

The third Parkinsons disease gene, PARK7, results from mutations in DJ1. The function of the protein encoded by DJ1 is not yet known, but it may be involved in oxidative stress responses Mutations in DJ1 are linked with autosomal recessive early-onset PD and at least initially appear to be a rare cause of familial PD, perhaps accounting for 1-2% of all early-onset cases. DJ1 is a highly conserved protein present in a diverse number of organisms and belongs to the DJ1/ThiJ/PfpI protein superfamily. The interaction of Parkin with DJ1 may involve a larger protein complex that contains CHIP (C-Terminus of HSC-70 Interacting Protein) and HSP70 (Heat Shock Protein-70), perhaps accounting for the lack of Parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ1 and Parkin, but this does not result in the ubiquitination or degradation of DJ1. Thus DJ1 and Parkin are linked in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD. A mutation in the gene PARK5 encoding UCHL1 is believed to be responsible for autosomal dominant Parkinsons disease. UCHL1 comprises 1% - 2% of all the proteins in the brain and can also be found in Lewy bodies. It is a de-ubiquitinating enzyme that hydrolyzes bonds between ubiquitins that have been attached to other proteins, to create monomeric (single) ubiquitin molecules. Mutation in the newly identified PINK1 is responsible for recessive forms of familial PD. PINK1 encodes a highly conserved, 581-amino acid, putative Serine/threonine protein Kinase and is a member of a small family of novel Kinases including CLIK1 (CLP-36 Interacting Kinase)/PDLIM1 coyness. PINK1 reduces neuronal apoptosis by reducing the release of CytoC (Cytochrome-c), thereby limiting the subsequent activation of Caspases9, -7, -3 and PARP (Poly (ADP-Ribose) Polymerase). The mitochondrial localization of PINK1 and the putative role that mitochondria play in PD neurodegeneration suggest that PINK1 may have amodulating effect on mitochondrially dependent cell death pathways. PINK1 may serve as a feedback modulator of the pro-apoptotic activity of PTEN, although PINK1 might also regulate other genes, proteins, and cell death pathways independently of PTEN (Ref.8 & 9).

Medications for Parkinsons disease act, in one way or another, to increase dopamine levels to make up for its loss caused by the death of the dopamine producing cells. Understanding of the pathophysiology of Parkinson disease has advanced rapidly over the last two decades through basic and clinical studies using modern neuroanatomical, clinical assessment, neuropathological and functional brain imaging methods. The clinical manifestations of Parkinsons disease, at least in early stages, reflect selective degeneration of dopamine neurons in the substantia nigra projecting through the nigrostriatal pathway to the caudal putamen with compensatory changes in this and related systems. Positron emission tomography with specific ligands for the dopamine system is a powerful tool for analysis of both degenerative and compensatory processes in the pathophysiology of Parkinson disease in vivo and can be used to confirm the diagnosis of dopamine deficient Parkinson disease. The increasing knowledge of the pathogenesis of Parkinsons disease at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression (Ref.10).