Osteopontin as a regulator of the inflammatory response to nigral celldegeneration

The cause of nerve cell death in the substantia nigra in Parkinson's disease remains unknown. However, one feature of the degenerative process is the onset of inflammation in this brain region due to the activation of another type of cell known as glia. Normally glial cells are essential for supporting the survival of the dopaminergic neurons, but when they become activated they start to secrete many different kinds of toxins that can then kill dopaminergic containing neurons and potentially contribute to the progression of the disease process. The biochemical mechanism known to occur involves an excessive activity of free radicals that induces oxidative stress and the production of Parkinson's disease. We have become interested in a protein called osteopontin that was first discovered in bone and subsequently found in blood and in kidney. The reason for our interest is that osteopontin is a protein that inhibits inflammation, controls oxidative stress, and reduces the production of nitric oxide. So we set out to see whether osteopontin was present in the substantia nigra and showed it to be present in normal rat brain and for its levels to be further increased by the induction of inflammation. We subsequently showed that osteopontin was also present in the substantia nigra of primates and that following induction of parkinsonian motor deficits in these animals by exposure to the toxin MPTP that the levels of osteopontin were raised and they were raised persistently over long periods of time. So we believe that osteopontin may be a previously unrecognized component of the inflammation that occurs in the substantia nigra in Parkinson's disease. We now propose to investigate whether osteopontin has a role in protecting dopaminergic neurons from degeneration induced by toxic insult and to establish the purpose of this protein within the substantia nigra. We will show how its increased production during the process of dopaminergic cell degeneration could be harnessed to produce a novel treatment for Parkinson's disease which will be effective in stopping or slowing its progression.