Selective Neuroprotective Effects of the S18Y Polymorphic Variant of UCH-L1

Promising Outcomes of Original Grant:
We were able to replicate in an in vivo setting in the nigrostriatal system our previous observation in neuronal cell cultures that lack of UCH-L1 did not alter sensitivity to mitochondrial toxins/oxidative stress, as a gad pre-clinical model lacking UCH-L1 did not show differential sensitivity to MPTP. We were unable however to verify the neuroprotective effect of S18Y UCH-L1 in an in vivo setting, as established protocols of adenoviral transduction within the striatum did not lead to detectable expression in nigral neurons. We have therefore had to modify the protocol of the injections, using striatal injections of higher doses of the adenoviruses at two separate sites and depths. Using this modified protocol, we have now achieved highly significant transduction of nigral neurons.

Objectives for Supplemental Investigation:
We will use the modified protocol of striatal injections to transduce pre-clinical model nigral dopaminergic neurons with GFP, WT UCH-L1 and S18 UCH-L1, and one week later we will administer MPTP or saline. We will examine effects on nigral domaminergic neuronal cell numbers by immunohistochemistry and stereological assessment two weeks later. This is similar to the original plan, with the difference that now we have an improved viral delivery protocol that achieves significant transduction within nigral neurons.

Importance of This Research for the Development of a New PD Therapy:
Oxidative stress and mitochondrial toxicity are thought to represent major pathogenetic mechanisms in Parkinson’s disease. If our current work establishes that expression of the polymorphic variant S18Y of UCH-L1 in nigral neurons affected in Parkinson’s disease is protective against such insults, this could open avenues for novel therapies that would try to boost expression of this variant or mimic its effects, once the mechanisms underlying this intriguing phenomenon are understood. This is especially important, as this variant is common, and it may affect the risk of developing Parkinson’s disease in certain populations.