Pathogenic Significance of the Hyperpolarization-activated Current (Ih) in the Degeneration of Dopaminergic Neurons
Rapid Response Innovation Awards, 2011
The neurotoxin MPTP is believed to kill nigral dopaminergic neurons by inhibiting mitochondrial metabolism, thus producing Parkinsonís signs in pre-clinical models. Recent studies have questioned this widely accepted theory, suggesting that other mechanisms could be involved. Our laboratory has found that MPTP also inhibits Ih, a cationic current largely expressed in these neurons, which has been proposed to correlate with sensitivity to MPTP. Based on these observations, we want to test the hypothesis that Ih inhibition is a mechanism of pathogenic and therapeutic relevance.
The goal of the present project is to answer the following question: is Ih inhibition a general pathogenic mechanism during the development of Parkinsonís? To this end we need to dissect the molecular mechanisms underlying the action of MPTP on Ih and to demonstrate that selective Ih inhibition in vivo is capable of inducing signs of Parkinsonís in experimental pre-clinical models. For the fulfillment of the first task we will employ electrophysiology and biochemistry techniques, while for the second task we will perform in vivo experiments where the nigral dopaminergic toxicity of Ih blockers will be compared with that of MPTP. Treated pre-clinical models will be screened with standard tests for motor skills as well as with electrophysiology and immunohistochemistry on dissected brains.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
Our research aims at uncovering the potential pathogenic significance of Ih inhibition in the MPTP model of Parkinsonís. If this phenomenon turns out to be a major determinant of MPTP toxicity, it will be possible to speculate that this mechanism is of general pathogenic significance in the development of human Parkinsonís as well. In this case, our study will have revealed a new molecular target of potential therapeutic interest.
We expect that the fulfillment of the aims stated above provides a significant improvement in the comprehension of the pathogenic mechanisms underlying Parkinsonís disease that eventually leads to the discovery of a treatable molecular target.
INTERIM PROGRESS REPORT
During this MJFF-supported research, we have identified a molecular mechanism potentially linking Ih loss of function and cell death in nigral dopamine neurons in vitro, the cellular basis of Parkinsonís disease. Furthermore, experiments on pre-clinical models indicate that the pathogenic relevance of this mechanism may extend to other forms of Parkinsonís and explain a distinctive feature of the disease, such as the preferential degeneration of nigral dopamine neurons. Further investigations, conducted with more sophisticated approaches, will hopefully consolidate the preliminary findings obtained so and confirm that Ih loss of function is a bona-fide pathogenic step in the degeneration of nigral dopamine neurons and onset of the disease, thus opening new therapeutic possibilities.
Presentations & Publications
1-methyl-4-phenylpyridinium (MPP+) modulates hyperpolarization-activated current (Ih) in substantia nigra pars compacta dopaminergic neurons. Masi A., Narducci R., Moroni F., Mannaioni G. (2011)† Program No. 882.03/V8. 2011 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2011. Online.
MPP+ modulates hyperpolarization-activated current (Ih) in dopaminergic neurons of the substantia nigra pars compacta. Masi A., Narducci R., Moroni F., Mannaioni. XXXV National Congress of the Italian Pharmacological Society† P-5-44. G. (2011)
1-Methyl-4-Phenylpyridinium (MPP+) Modulates Hyperpolarization-Activated Current (Ih) In Substantia Nigra Pars Compacta Dopaminergic Neurons Masi A., Narducci R., Moroni F. & Mannaioni G. Presentation Code: p101.15 - Abstract Number: 1356 - Poster Board Number: C15 FENS Abstract, Volume 6, p101.15, 2012.
Parkinsonizing toxin 1-methyl-4-phenylpyridinium enhances temporal summation of excitatory post-synaptic potentials in midbrain dopamine neurons by inhibiting Ih. Narducci R,† Masi A., Landucci E., Moroni F., Mannaioni G.† Program No. 807.04/G11. 2013 Neuroscience Meeting Planner. San Diego. Society for Neuroscience, 2013. Online.
MPP(+) -dependent inhibition of Ih reduces spontaneous activity and enhances EPSP summation in nigral dopamine neurons. Masi A, Narducci R, Landucci E, Moroni F, Mannaioni G. Brit J Pharmacol. 2013 May 169(1):130-42.
Postdoctoral fellow at University of Florence
Location: Florence, Italy
Associate Professor at University of Florence
Location: Florence, Italy