Neurochemistry Changes Associated with Mutations in Familial Parkinsons Disease

M.      M. Siddique; E.      K. Tan

doi:10.2174/092986710793361270

Abstract

Parkinsons disease (PD), a common neurodegenerative disease, is characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. The exact role of genetic and environmental factors in the pathogenesis of PD has frequently been debated. The association of MPTP (methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine) and toxins (such as rotenone) with parkinsonism highlights the potential etiologic role of environmental toxins in disease causation. The recent discoveries of monogenic (such as α-synuclein, Parkin, UCHL1, PINK1, DJ-1, LRRK2) forms of PD have provided considerable insights into its pathophysiology. Parkin, an ubiquitin protein ligase assists in the degradation of toxic substrates via the ubiquitin proteasome system. It can also mediate a nondegradative form of ubiquitination. PINK1 and LRRK2 are possibly involved in the phosphorylation of substrates important for various cellular functions. Some toxins could interact with α-synuclein, an endogenous protein that is implicated in pathology of PD. Increasing in vitro and in vivo studies suggest that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction underpin the pathogenesis of sporadic and familial forms of PD. Elucidation of the functions of the proteins encoded by the diseasecausing genes will provide an opportunity for identification of specific pathways that could be targeted in neurotherapeutics.

Keywords: Parkinson's disease (PD), protein aggregation, apoptosis, mitochondrial dysfunction, Neurochemistry, Mutations, Lewy bodies, neurites, MPTP, rotenone, pathophysiology, PINK1, LRRK2, phosphorylation, SNpc, UPS, Synuclein, synucleinases, SIAH-1, Microglial, ROS, FeCl2, DA, exocytosis, NF-B, Bcl-2, Parkin, Depolymerization, toxins, ubiquitin, Dopamine, protein, RanBP2, homeostasis, PI3K, UCH-L1 (PARK5), PINK-1, TRAP1, Granzyme M, Cytochrome C, HtrA2, XIAP, Akt1, Akt2, DJ 1, Drosophila, leucine-rich repeat kinase 2, GTPase, G2385R, PTM, Dictyostelium discoidum, ERM, RNAi, ATP13A2, lysosomal, neurotoxicity, OHDA, ATM, E2F, toxicity, HSPs, AIF