α-Synuclein: A therapeutic target for Parkinson's disease?

Parkinson's disease is a progressive age-related neurodegenerative disease with invariant loss of substantia nigra dopamine neurons and striatal projections. This disorder is well known for the associated motoric symptoms including resting tremor and the inability to initiate movement. However, it is now apparent that Parkinson's disease is a multisystem disorder with patients exhibiting symptoms derived from peripheral nervous system and extra-nigral dysfunctions in addition to the prototypical nigrostriatal damage. Although the etiology for sporadic Parkinson's disease is unknown, information gleaned from both familial forms of the disease and animal models places misfolded alpha-synuclein at the forefront. The disease is currently without a cure and most therapies target the motoric symptoms relying on increasing dopamine tone. In this review, the role of alpha-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. (c) 2008 Elsevier Ltd. All rights reserved.