The objective of the proposed research is to test the ability of novel sirtuin inhibitors to protect against dopamine neuron toxicity in a pre-clinical model of Parkinson's disease. Sirtuins are highly conserved proteins that are thought to be involved in aging and neurodegerative disease. Recently, potent inhibitors of SIRT2 have been discovered and shown to rescue α-synuclein-induced toxicity in both cellular and fly models of PD. These findings suggest that targeting SIRT2 may be therapeutically beneficial not only for PD, but other neurodegenerative disorders.
Using a viral-vector based model of α-synuclein overexpression in the rat, we will test the ability of the SIRT2 inhibitor, AK-1, to prevent progressive dopaminergic neurotoxicity. Rats will first be injected with a recombinant adeno-associated virus to overexpress α-synuclein in the substantia nigra. Synuclein overexpression causes progressive and selective degeneratation of nigral dopamine neurons and formation of intracellular protein aggregates reminiscent of Lewy bodies found in PD patients. After 2 weeks, rats will be implanted with a brain infusion pump and chronically treated with either AK-1 or vehicle control for at least 4 weeks. At the end of treatment, we will assess rats for dopamine neuron toxicity both in the substantia nigra and in stiatal projections. SIRT2 inhibitors may rescue α-synuclein toxicity by increase in inclusions, thus we will also correlate toxicity with aggregate formation.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Studies to date on SIRT2 inhibitors have been limited to cellular and fly models of PD. These findings are significant and identify a potentially novel approach to treating PD and related disorders. Testing in a mammalian system is a crucial step toward establishing whether SIRT2 inhibitors may be therapeutic in PD. The results of the proposed experiments will likely influence whether SIRT2 inhibitors are pursued by pharmaceuticals and spur further development and optimization of these drugs for potential use in patients.
We hypothesize that the SIRT2 inhibitor, AK-1, will prevent α-synuclein-induced dopamine neuron toxicity in our pre-clinical model of PD. Rescue of dopamine neurons may also be associated with increase in α-synuclein aggregates.
Recent data indicates a possible role for alpha-synuclein in the nucleus in neurotoxicity. Targeting alpha-synuclein in the nucleus appears to increase toxicity in PD models, likely through interacting with proteins in the nucleus called histones. Recently, potent inhibitors of the enzyme SIRT2, which also interacts with histones, have been discovered and shown to rescue alpha-synuclein-induced toxicity in both cellular and Drosophila models of PD. These findings suggest that novel SIRT2 inhibitors may be therapeutically beneficial for PD.
In this study we tested whether the SIRT2 inhibitor, AK-1, could protect against alpha-synuclein-induced dopaminergic toxicity in a pre-clinical model of PD. Using a targeted viral model of alpha-synuclein overexpression in the substantia nigra, we examined the effect of chronic administration of AK-1 on nigrostriatal toxicity.
Our results show no significant protection of dopamine cell loss in the substantia nigra. However, some evidence suggests possible protection of nigrostriatal terminal plasticity and neurochemical function. Although preliminary, these data provide limited evidence for possible neuroprotection by a novel SIRT2 inhibitor in a vertebrate model of PD.