In the initial stage of Parkinson's disease, patients' movements are
stiff and slow. This can be remedied with the drug L-dopa, but after a
few years of treatment, patients usually develop uncontrolled jerking
motions known as dyskinesias. Other diseases, such as Huntington's
disease and several hereditary conditions, are also associated with
movement disorders of this kind.
The striatum plays an important role in movement
control. But which neural pathways are most important has been hotly
debated.In order to drive a car, you need a good balance between accelerator
and brake. The same applies to a part of the brain - the striatum - that
controls our movements.
‘The new discovery on the interaction between the "accelerator" and the "brake" in the striatum may guide the development of treatments for movement disorders.’
Research at Lund University in Sweden has led
to new findings on the interaction between the "accelerator" and the
"brake" in the striatum. These findings may guide the development of
treatments for movement disorders.
An innovative approach
The striatum has two principal types of cells forming distinct
neural pathway, termed "direct pathway" and "indirect pathway",
respectively. The research debate has centred on whether both pathways
are equally important in all situations, and whether they need to
cooperate or can work independently. To address this question, the Lund
researchers applied a method called chemogenetics.
Using a harmless
virus, they introduced a new gene into one or the other type of striatal
cell in laboratory mice. The gene coded for the production of a
receptor protein activating the relevant neural pathway. However, the
receptor became stimulated only when the animal was administered a
particular substance whose effect lasted a couple of hours.
method, the researchers were able to control the activity of cells
forming the direct or indirect pathway while studying the animals'
behavior. Studies were conducted on both normal mice and animals with a
Parkinson's-like injury, and both with or without L-dopa.
The results showed that all types of movements were controlled by
both pathways, which proved to function as a sort of "accelerator" (the
direct pathway) and "brake" (the indirect pathway), respectively. In
Parkinson's mice treated with L-dopa, activation of the direct pathway
produced faster movements but also more severe dyskinesias, mimicking
both the advantages and the disadvantages of Parkinson's therapy. On the
other hand, activation of the indirect pathway gave slower movements
but also eased the dyskinesias caused by L-dopa.
"We interpret these results to mean that the pathways need to
interact in all situations, even in Parkinson's-like conditions and upon
L-dopa treatment. You can't have only acceleration and no braking, but
must instead balance both functions in a precise manner", says Parkinson's researcher Angela Cenci Nilsson in Lund.
The results could inform both basic and therapeutic research
She believes that L-dopa therapy gives complications when it
"inactivates the brake" by strongly inhibiting the indirect pathway,
while "pressing too hard on the accelerator" by overstimulating the
direct pathway such that dyskinesias can occur.
These new findings could explain why it has been difficult to
develop new drugs for Parkinson's disease. Drug development in recent
years has been directed towards one or the other neural pathway, whereas
this study points to a need to intervene on both pathways using either a
drug that regulates both of them or two complementary drugs.
"Our results could be of great significance both for basic research and for therapeutic research", says Angela Cenci Nilsson.