The abnormal proteins present in specific brain cells of patients with several neurodegenerative diseases including Alzheimer disease (AD), Huntington disease (HD), Lewy body dementia, and PD are attracting attention as potential drug targets. Controversy still exists, however, as to whether they are the root cause of these diseases or the result of upstream events. Yet, these proteins may prove to be more promising and discrete targets for new drugs than neurotransmitter systems.
Robert L. Nussbaum, M.D., and Christopher E. Ellis, Ph.D., pointed out, in a 2003 article in The New England Journal of Medicine, that the genetic mapping and gene-isolation tools created by the Human Genome Project greatly accelerated the rate of identification of genes involved in the rare inherited forms of PD and AD. These same tools and their more sophisticated descendents are now being used to determine the genetic contributions to the more common, multifactorial forms. They revealed alpha-synuclein as a neurotoxic in PD and believe that it may explain the pathogenesis not only of the inherited form of PD but also of the idiopathic form.
Alpha-synuclein is a major component of the filamentous inclusions called Lewy bodies, protein clumps that are the pathological hallmark of PD. The normal function of alpha-synuclein remains unknown, although it is thought to play an important role in synaptic function or lipid binding. Synuclein usually remains in an unfolded state but is highly prone to aggregation.
The Michael J. Fox Foundation (MJFF) has invested about $12 million to date in alpha-synuclein. It supports researchers working to characterize the protein's role in PD, assess its potential as a target for neuroprotective therapies, and develop drugs that inhibit aggregation of synuclein filaments into clumps.
No drugs targeting alpha-synuclein have reached the clinic, according to the MJFF. Some approved compounds, though, have been shown to stop synuclein clumping and to break up clumps in vitro. Even sirtuins are getting into the act, as investigators reported discovery of a potent sirtuin 2 (SIRT2) inhibitor that rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of PD.