Journal of Pharmacy Research Vol.5 Issue 11.November 2012 Rupesh K. Gautam et al. / Journal of Pharmacy Research 2012,5(11),5188-5193 5188-5193 Review Article ISSN: 0974-6943 Available online through www.jpronline.info * Corresponding author. Rupesh K. Gautam Department of Pharmacology Jaipur College of Pharmacy, ISI-15, RIICO, Institutional Area, Tonk Road, Sitapura, Jaipur-302022, India. Parkinson’s Disease – A Molecular Approach Rupesh K. Gautam*, Prafulla C Tiwari, Ahamed Noor Mansoori, Tarun Biswas, M.M.Gupta 1 Department of Pharmacology, 1 Department of Pharmaceutics, Jaipur College of Pharmacy, ISI-15, RIICO, Institutional Area, Tonk Road, Sitapura, Jaipur-302022, India. Received on:19-07-2012; Revised on: 11-08-2012; Accepted on:24-09-2012 ABSTRACT Parkinsonism is a clinical syndrome consisting of four cardinal features: bradykinesia (slowness and poverty of movement), muscular rigidity, resting tremor (which usually abates during voluntary movement), and an impairment of postural balance leading to disturbances of gait and falling. The pathological hallmark of Parkinson Disease (PD) is a loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta, with the appearance of intracellular inclusions known as Lewy bodies. Progressive loss of dopamine-containing neurons is a feature of normal aging; however, most people do not lose the 70% to 80% of dopaminergic neurons required to cause symptomatic PD. Without treatment, PD progresses over 5 to 10 years to a rigid, akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism.The availability of effective pharmacological treatment has altered radically the prognosis of PD; in most cases, good functional mobility can be maintained for many years, and the life expectancy of adequately treated patients is increased substantially. It is important to recognize that several disorders other than PD also may produce parkinsonism, including some relatively rare neurodegenerative disorders, stroke, and intoxication with dopamine-receptor antagonists. Drugs in common clinical use that may cause parkinsonism include antipsychotics such as haloperidol and thorazine and antiemetics such as prochloperazine and metoclopramide. In this review, we have also discussed about the Genetic Predispositions of Parkinson’s Disease. Key words: Parkinson’s disease (PD), CNS disorders, Parkinsonism. Figure 1: Parkinson’s disease is characterized by loss of Dopaminergic Neurons from Striata. I NTRODUCTI ON Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of neurons from substantia nigra pars compacta (SNPC) of basal ganglia in mid brain [1] . Degeneration of neurons of substantia nigra leads to deficiency of Dopamine which normally sends signal to coordinate body movements. Clinically it is characterized by: 1. Trembling of hands, arms, legs, jaw, and face 2. Stiffness of the arms, legs and trunk 3. Slowness of movement 4. Poor balance and coordination Pathophysiology The primary cause behind Parkinson’s disease (PD) is loss of the neurons in the substantia nigra pars compacta (snpc) that provide dopaminergic innervation to caudate and putamen nuclei in basal ganglia of mid brain. For development of symptomatic PD, there should be loss of more than 80% dopamine content in striata [1] . LRRK2 function on actin and microtubule dynamics in PD Mutations in LRRK2 gene lead to PD phenotypes with strong overlap to typical late onset disease that neuropathologically is characterized by the presence of ß-synuclein-positive Lewy bodies. Therefore, the understanding of LRRK2-related pathology may unravel the cellular events underlying PD. LRRK2 protein is a large protein of 2,527 amino acids and consists of several domains including a N-terminal leucine rich repeat region, ankyrin and C terminal WD40 domain that possibly mediates protein- protein interaction. It combines a functional GTPase domain called Roc domain (Ras complex protein) and kinase domains making up one molecule. Mutations associated with PD have been described throughout all LRRK2 domains. The main genetic cause of PD found thus far is the G2019S substitution that lies in the activation segment of the kinase domain. In the brain, LRRK2 is expressed in neurons, astrocytes and microglia. Recent studies have detected LRRK2 in specific brain regions including the cortex, striatum, hippocampus, cerebellum and as well as in dopaminergic neurons of the substantia nigra. At subcellular level, it was found mainly in the cytoplasm, lipid rafts, lysosomes, endosomes, mitochondria, and in association with Golgi transport vesicles. Soon after the cloning of LRRK2 and in the absence of a physiological protein substrate, a number of in vitro studies attempted to evaluate the kinase activity of LRRK2 and to examine how the PD-related mutations modulate its activity. First description of a potential functional role of LRRK2 is shown in work of McLeod and colleagues where they associated LRRK2 kinase activity with the maintenance of neuronal process. They demonstrated by using both neuronal cultures and by delivering the wild-type (wt) and G2019S kinase domain into rat brains that the neurons with G2019S mutation but not with LRRK2 had shorter neuritis. Suppression of LRRK2 expression by shRNAs led to an increase in neurite length. Furthermore, they established a connection between LRRK2 and the MTs-associated protein tau by showing that the expression of G2019S mutation led to tau-positive inclusions and also co localized with tau in these inclusions. In 2007, an elegant biochemical work reported the protein moesin as the first substrate for LRRK2 kinase activity in vitro. Kinase substrate tracking and elucidation screening (KESTRE) was used in rat brain extracts in order to identify