Funded Studies
Objective/Rationale:
The accumulation of at least two toxic products in the brain called DOPAL and 4HNE results in death of neurons that are implicated in Parkinson’s Disease (PD). We identified a novel drug-like molecule (called Alda) that activates a brain enzyme called aldehyde dehydrogenase (ALDH). Activation of ALDH leads to a better removal of the neurodegenerative toxins. We propose to use Alda in two animal models of PD and determine whether enhances detoxification of 4HNE and DOPAL in neuron cells can slow down the development of PD.
Project Description:
We will use the DOPAL-induced pre-clinical model of PD where DOPAL is injected into rat substancia nigr (SN). DOPAL will be injected together with the ALDH activator alda-1 or with the ALDH inhibitor disulfiram. Two control groups will be used: one group of rats will be injected with alda-1 alone and the other group will be injected with vehicle alone. After treatment, the brain tissue of rats will be isolated and the viability of the dopaminergic neurons in the SN, the levels of 4HNE in the brain tissue, the levels and activity of ALDH, and the amount of aldehydic adducts and alpha-synuclein aggregates will be determined. Rats in each group will also be subject to behavioral tests.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The current standard of care for PD patients is L-DOPA treatment. While effective in the short term, patients who take L-DOPA eventually have continued progression of PD, due to continued loss of dopaminergic neurons in the SN. If activating ALDH can reduce the level of toxic aldehydes that accumulate in dopaminergic neurons and enhance their survival, then this may be a therapy that can actually slow or stop PD.
Anticipated Outcome:
By increasing ALDH activity in the dopaminergic neurons of the SN, we expect to observe a larger number of healthy dopaminergic neurons. Conversely, inhibiting ALDH activity by treatment with disulfiram should increase DOPAL-induced damage. Behaviorally, animals treated with an ALDH activator should exhibit the fewest PD symptoms. Based on the results of these experiments we will learn the importance of ALDH in the pathogenesis of PD and whether or not ALDH activation can help slow or stop PD development.
Progress Report
A role of aldehydes in cell toxicity in general and in neuronal toxicity in particular has been previously suggested. Environmental aldehydes can contribute to this toxicity, but aldehydes are also generated by oxidative stress. In dopaminergic neurons, metabolism of dopamine by the monoamine oxidase generates a particularly toxic aldehyde, DOPAL. All cells have a natural mechanism to detoxify these toxic aldehydes; a set of enzymes, called aldehyde dehydrogenases, are present in different cell compartments and contribute to aldehyde detoxification. Unfortunately, aldehyde dehydrogenases are themselves sensitive to aldehyde-induced inactivation. We have tested the hypothesis that accelerating aldehyde detoxification by a newly identified small molecule aldehyde dehydrogenase activator, Alda-1, will reduce neuronal damage in models of Parkinsonism, in culture and in vivo. Our early studies are encouraging and further research will be conducted to examine the potential therapeutic effects of novel molecule ALDH activators that we have identified.
Final Outcome
We used the MPTP-induced Parkinsonism in pre-clinical models to test the hypothesis that activation of an important detoxifying enzyme in the mitochondria, called aldehyde dehydrogenase can be used as a novel therapeutic approach to Parkinson’s disease. However, the use of MPTP to induce Parkinsonism in pre-clinical models led to conflicting results. Although we observed a decline in both dopamine and dopaminergic neurons after MPTP injections, there was no decline in aldehyde dehydrogenase activity or increase in the harmful aldehydes that are associated with the disease in humans. Not surprisingly, our attempt to prevent loss of dopamine and dopaminergic neurons in the brain with activation of aldehyde dehydrogenase failed using this MPTP model. Importantly, the characteristic motor deficits associated with Parkinsonism were NOT observed in these models despite the massive loss of dopaminergic neurons in the brain. Our earlier data in pre-clinical models and further studies in cultured neurons lead us to believe that activation of the enzyme aldehyde dehydrogenase constitutes an important route to treat Parkinson’s disease but the use of pre-clinical models that better recapitulate the disease in humans is necessary to properly test our hypothesis.