Drosophila Parkinson's disease model for Investigating Sleep Disorder of PD - Thesis Example

?"Using a LRRK2 Drosophila Parkinson's disease model to investigate sleep disorder/dysfunction (non motor symptoms) of PD" Aim Elaborating a researchproposal encompassing investigation of sleep patterns (specific non motor symptom) pertaining to the dopamine (and serotonin) neuron function in a Parkinson's disease model. Introduction Parkinson’s disease (PD) is an advancing and persisting neurodegenerative disorder that influences the control of the central nervous system (CNS) on the voluntary movement. It was first reported by James Parkinson in 1817, as “An Essay on the Shaking Palsy” (Parkinson, 2002). Much research has been carried out in two centuries towards understanding Parkinson’s disease but no definite cure could be attained so far. PD has emerged as the second most prevalent neurodegenerative disease after Alzheimer’s disease (AD). Diagnosis of Parkinson’s disease is difficult in early stages of the disease. Estimates reveal that only 75% of the clinically diagnosed cases are confirmed at autopsy (Gelb, 1999). Although the disease is non fatal but the linked complications culminate into life threatening consequences especially in the later stages of the disease (Morgante, 2000). The neuropathological studies disclose characteristics of PD and its connection with neuronal degeneration in substantia nigra pars compacta (SNpc), loss of dopaminergic neuron results in imbalance between dopamine and acetylcholine. As less amount of dopamine is secreted, there is overtone of cholinergic activity in basal ganglia, responsible for various clinical features of Parkinson’s disease. These theories have been confirmed by autopsies carried on patients suffered from PD and also drugs (Levodopa) enhancing dopaminergic neurotransmission in brain are effective in treatment of Parkinson’s disease (Carlsson, 1958). The possible reasons that emerged for the pathogenesis of the condition encompass, PD-linked thrashing of dopaminergic neurons, different than the normal aging process (Fearnley, 1991). Further confirming the loss of nigrostriatal dopaminergic neurons in midbrain, and existence of Lewy bodies (intraneuronal proteinacious cytoplasmic inclusion) in the present neurons (Dauer, 2003). SNpc enclose neuromelanin responsible for the pigmented appearance and loss of dopaminergic neurons could be linked with SNpc depigmentation (Marsden, 1983). Lewy bodies are associated with neurological conditions, they enclose protein components of the ubiquitin proteosome system (UPS), hsp, neurofilaments, ?-synuclein and synphilin-1 (Olanow, 2004). Cardinal features of Parkinson’s disease is associated with motor symptoms encompassing resting tremor, rigidity, bradykinesia/ akinesia, shakiness in posture, gait and posture disturbances may be common including shuffling of the feet, decreased arm swing and stooped forward- flexed posture, pin rolling movements of thumb, drooling of saliva from mouth, expression less face or masked face, micrographia, impaired agility (Nussbaum, 1997). The non motor symptoms occur due to loss of non-dopaminergic pathway resulting in the distress in the patient and hence impairing life (Hely, 2005). Mood alteration is common in PDs, including depression (Lieberman, 2006), anxiety, cognitive disturbance, impaired attention, prioritizing, interpreting social cues, and subjective awareness, dementia, hallucination, delusion, short term memory loss, enhanced sexual activity and psychosis (Frank, 2005; Levin, 2005). Sleep disturbances, disproportionate daytime sleepiness with nighttime sleeplessness, distressed REM sleep (Freedom, 2007). Disturbed visual sensations, spatial analysis and color differentiation, PD cases are unaware of their body position (Adler, 2005). Nocturia, orthostatic hypotension, distorted weight (Martignoni, 1995). Risk Factors for Parkinson’s disease encompass advancing age, environmental predisposition, and genetic factors in the select genes. The onset of Parkinson occurs in the individual above 50 years. The cause of PD is idiopathic and genetic alteration has emerged as the most convincing reasons for the induction of PD. Family history or PD serves as a risk factor for the onset of PD. (Semchuk, 1993). Genes associated with Parkinson After mapping of ten chromosomal regions called PARK encompassing, two autosomal dominant genes, ?-synuclein and leucine –rich repeat kinase 2 (LRRK2) genes, moreover three autosomal recessive genes, parkin, DJ-1, phosphatase and tensin (PTEN)- induced kinase 1 (PINK 1) are found to be associated with the Parkinson’s disease (Solano, 2000). It is manifested that these genes are responsible for only a few proportion of PD cases, however the products of these genes, i.e. the proteins are responsible for random appearance of PD cases. These studies could be extrapolated using animal models. The genes responsible for familial PD encompass, PINK1, DJ-1, parkin, ?-synuclein, UCH-L1, LRRK2. While the cellular pathways leading to the neuronal death encompass mitochondrial dysfunction for PINK1 and DJ-1, DJ-1 and parkin are also found to be associated with the oxidative stress, leading to the neuronal cell death. parkin is also found to follow aggregation of protein molecules, this property is also shared by ?-synuclein molecules and UCH-L1 to bring neuronal cell death. UCH-L1 is found to be associated with the Ubiquitin Proteosome System (UPS) dysfunction to bring neuronal cell death while the cellular mechanism of most recently discovered LRRK2 is yet to be firmly established (Fortin, 2004). Studied divulge that mutation of ?-synuclein modify the characteristics of protein and this modification leads to accumulation of the protein molecules (Conway, 1998; Choi, 2004). Accumulation of ?-synuclein protein leads to the configuration of cytoplasmic inclusions called the Lewy bodies (Spillantini, 1997). It is therefore established that ?-synuclein alterations is a major contribution for the nonfamilial forms of the disease condition. Leucine-rich repeat kinase (LRRK2) gene Leucine-rich repeat kinase (LRRK2) gene located on chromosome 12q12, linked to PARK8 locus was found to be associated in many Parkinson's cases, highlighting its prevalence (Zimprich, 2004; Paisan-Ruiz, 2005). Also called dardarin, encompass 2,527 amino acids with 51 exonic sequences. Research reveals the genetic predisposition to be more predominant for causing PD and its pathological implications. LRRK2 gene is of paramount significance as it has emerged as a foremost basis of autosomal dominant forms of PD and are accountable for a noteworthy amount of sporadic cases. Understanding for domain structure of the leucine-rich repeat kinase (LRRK2) gene imply that it has 13 LRRs, tag on to this is Roc, next to this is COR and MAPKKK domains and c-terminus encloses WD40. The gene bank accession is AAV63975 for human LRRK2 (Mata et al, 2006). Mutation in leucine-rich repeat kinase (LRRK2) gene has been established as the cause of late onset autosomal dominant PD. Expression of this mutant LRRK2 results in the neuronal degeneration, pleiomorphic pathology comprising nigral degeneration, neurofibrillary tau-positive tangles and Lewy bodies (Paisan-Ruiz, 2004; Rajput, 2006; Ross, 2006; Zimprich, 2004). Studies on the animal models suggest that these genes have potential role in neuron specific function (Carmine, 2006). Further, studies postulate that in familial PD cases the inherent and extrinsic lethal insults, predominantly distressing for midbrain dopaminergic neurons (Betarbet, 2002). Initial findings prevail that a mutation in the ?- synuclein gene was the first gene to be identified as a causative factor for PD, however, mutations in this gene are very rare cause of disease (Farrer, 2007). Mutation in the parkin gene were reported to be associated with the autosomal recessive juvenile parkinsonism (Katida, 1998). Parkin mutation account for ~50% familial cases and ~70% of sporadic cases with age at onset Read More