Research opens the door to new therapeutic options for Parkinson's disease

These advances have been reported in a new scientific article published in the international journal Nature, fruit of the collaboration between Northwestern University (Chicago), Weill Cornell Medical College (New York) and the Institute of Biomedicine of Seville HUVR/CSIC/US/ and Ciberned.

As a result of the research led collaboratively and on a multicenter basis by Patricia González-Rodríguez during her stay at Northwestern University (Chicago, USA), a new article has been published in the international journal Nature that opens the door to new ways to investigate therapeutic options hitherto not considered for Parkinson's disease.

After years of research, data have been released about Parkinson's disease that may change the course of the disease and consequently of the patients who suffer from it. On the one hand, the researchers conclude that it is insufficient to affect just part of the dopaminergic neurons (axons) as previously thought, but must also affect the body of the cell itself (soma). Furthermore, it has been observed that the neurons affected by the disease do not die, they only lose some of their properties. Consequently, they could be reactivated with potential new and future treatments.

These results were obtained from a genetically modified mouse in 2015, in the research project that researcher Patricia González-Rodríguez conducted together with the laboratory team led by José López Barneo at the Institute of Biomedicine of Seville/CIBERNED and which is, at present, the first known animal model that replicates Parkinson's disease in humans. Specifically, the animal model, lacking the Ndufs2 gene, alters the mitochondrial complex I (CMI) and generates progressive parkinsonism (abnormal movements) in mice. This mouse model fills an important need in the disease research community.

The causes of Parkinson's disease are currently unknown, although they have traditionally been associated with defects in a molecular complex called CMI in the dopaminergic neurons of the substantia nigra pars compacta. The absence of a suitable animal model to test this hypothesis has been an obstacle to advacing knowledge about the causes of Parkinson's disease, generating controversy in the field of Parkinson's disease, without knowing whether the defects in CMI were a cause or a consequence of the disease.

This article also describes how neurons affected by the disease lose some of their properties and change their metabolism for a long time. This data is important because of the previous belief in the scientific community that the affected neuron died from the disease with no chance of recovery. This paradigm shift opens the door to a wealth of research avenues for new therapeutic treatments.

Characteristics of the animal model

The model presents a regionally selective pathology, i.e., first the axon of dopaminergic neurons is affected and then the soma (cell body). The study also describes how it is insufficient for the axons of the dopaminergic neurons to be affected (and malfunction) for Parkinsonism to occur. Rather the soma has to be affected also.

For more than thirty years, the prevailing view among scientists studying the disease has been that the cardinal motor symptoms are caused by depletion of dopamine in the axons. However, contrary to this school of thought, this research describes how a lack of dopamine in the soma (cell body) region of the neurons, called the substantia nigra, is necessary for the motor symptoms of Parkinson's disease to appear.

Results from this paper's basic research have led to a clinical study in Parkinson's patients in collaboration with Michael Kapplit, a neurosurgeon at Weill Cornell Medical College (New York) and co-author of this article in Nature. This gene therapy will be directed to treat this small area of the brain, called the substantia nigra, where the soma (body) of the neurons is located instead of the axons as had been done until now.

"The ultimate goal is to better understand the pathophysiology of Parkinson's disease and contribute with this knowledge to the development of novel therapies that will improve the quality of life and life expectancy of patients," says Patricia González, who will soon return to the Biomedicine Institute of Seville to continue working with José López Barneo, who was her mentor during her thesis and subsequent postdoctoral studies at IBiS.