It is known that neurodegenerative diseases such as Parkinson’s cause the gradual death of brain neurons. But what exactly are the mechanisms that go awry to cause degeneration of nerve cells? A team of researchers from Université Laval and the Quebec Mental Health Research Institute investigated the matter and show, in an article in Proceedings of the National Academy of Sciences (PNAS), the role played by two key regulatory proteins in the cascade of reactions leading to the death of neurons in Parkinson’s disease.
One of the main manifestations of Parkinson’s is the selective degeneration of neurons that produce dopamine, a neurotransmitter that intervenes in the initiation and control of movement, explains the study leader, Martin Lévesque. The specificity of these neurons is due to proteins, called transcription factors, which cause selective expression of certain genes during embryogenesis. “Some of these transcription factors, like Lmx1a and Lmx1b, continue to be expressed in the adult brain, almost exclusively in dopaminergic neurons, but their functions were unknown. ”
To shed some light on the question, the researchers used two approaches to block the expression of Lmx1a and Lmx1b in the brains of laboratory mice. “The impact of this blockage is very similar to what is observed in the brains of people with Parkinson’s,” says Prof. Lévesque. Indeed, the researchers first noted that in absence of these two transcription factors, some functions of mitochondria do not occur normally. Then there is formation of protein aggregates, called Lewy bodies, and progressive degeneration of dopaminergic neurons. “These manifestations, typical of Parkinson’s, are observed in the same brain region than in humans,” says the researcher.
By comparing the expression profile of genes in normal mice and mice in which Lmx1a and Lmx1b had been blocked, the researchers found that the two transcription factors were involved in the expression of a protein called NRF1, which is associated with mitochondrial genes. “When we then reintroduced NRF1 in the brains of mice without Lmx1a and Lmx1b, using a viral vector, it prevented the degeneration of more than 80% of dopaminergic neurons. In addition, the mice did not show any of the usual behavioral manifestations of Parkinson’s, “says Prof. Lévesque.
The results of this study open interesting perspectives on many fronts. First, the researchers now have a new animal model that reproduces well the main manifestations of Parkinson’s, which should facilitate research in the field. In addition, new therapeutic targets against Parkinson just appeared on the radar screen. The current work of Professor Lévesque’s team aims to deepen the potential of Lmx1a, Lmx1b and NRF1 in the treatment of Parkinson’s.
The study published in PNAS is signed by 17 researchers, including Hélène Doucet-Beaupré, Catherine Gilbert, Marcos Schaan Profes, Audrey Chabrat, Véronique Rioux, Julien Charest, Francesca Cicchetti, Martin Parent and Martin Lévesque, from Université Laval.
Source of text: Jean Hamann, Le Fil de l’Université Laval
Original research article:
Doucet-Beaupré H, Gilbert C, Profes MS, Chabrat A, Pacelli C, Giguère N, Rioux V, Charest J, Deng Q, Laguna A, Ericson J, Perlmann T, Ang SL, Cicchetti F, Parent M, Trudeau LE, Lévesque M. Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons. Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):E4387-96. doi: 10.1073/pnas.1520387113.