Parkinson’s disease (PD) results primarily from the 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced do death of dopaminergic neurons in the substantia nigra. paminergic neurodegeneration. Exposure of humans to Current PD medications treats symptoms; none halt or MPTP causes a syndrome that mimics the core neuroretard dopaminergic neuron degeneration. Although the etiology for sporadic Parkinson’s disease is unknown, information gleaned fromboth familial forms of the disease and animal models places misfolded _-synuclein at the forefront. The disease is currently without a cure and most therapies target themotoric symptoms relying on increasing dopamine tone.
Association of alpha-synuclein with oxidized lipid metabolites can lead to mitochondrial dysfunction in turn leading to dopaminergic neuron death and thus to Parkinson’s disease. Parkinson’s disease is the second most common neurodegenerative disease, after Alzheimer’s disease, among the aging human population. Substantial evidence links α-synuclein, a small highly conserved presynaptic protein with unknown function, to both familial and sporadic Parkinson's disease (PD). α-Synuclein has been identified as themajor component of Lewy bodies and Lewy neurites, the characteristic proteinaceous deposits that are the hallmarks of PD. Alpha-synuclein is a 140 amino acid neuronal protein that has been associated with several neurodegenerative diseases. A point mutation in the gene coding for the a-synuclein protein was the first discovery linking this protein to a rare familial form of Parkinson’s disease (PD).
The role of synuclein in disease pathogenesis and as a potential therapeutic target focusing on toxic conformers of this protein is considered. The addition of protofibrillar/oligomer-directed neurotherapeutics to the existing armamentarium may extend the symptom-free stage of Parkinson’s disease as well as alleviate pathogenesis. the different aggregation states of α-synuclein, the molecular mechanism of its aggregation, and the influence of environmental and genetic factors on this process. Abnormal processing of a-synuclein is predicted to lead to pathological changes in its binding properties and function. Various mechanisms for in vitro and in vivo a-synuclein aggregation and neurotoxicity are summarized, and their relevance to neuropathology is explored.
Keywords: Dopamine transporter, Tyrosine hydroxylase, Iron, Muscarinic receptors, Endocytosis, α-Synuclein, Therapeutics Oligomers, Protein misfolding.