Sonic hedgehog protein pathway stimulation could help Parkinson's
patients

Date:
September 22, 2021
Source:
The Graduate Center, CUNY
Summary:
Levodopa, or L-dopa, is considered the most effective treatment
for Parkinson's disease today. After a few years of treatment,
however, almost all patients develop a debilitating side-effect
called L-dopa induced dyskinesia, or LID, which causes involuntary
movements in the limbs, face, and torso. Deep brain stimulation
can alleviate LID, but the procedure is highly invasive and not
all patients are eligible.



FULL STORY ========================================================================== Levodopa, or L-dopa, is considered the most effective treatment for
Parkinson's disease today. After a few years of treatment, however,
almost all patients develop a debilitating side-effect called L-dopa
induced dyskinesia, or LID, which causes involuntary movements in the
limbs, face, and torso. Deep brain stimulation can alleviate LID, but
the procedure is highly invasive and not all patients are eligible.


==========================================================================
Now, a new study led by researchers at the Graduate Center, CUNY and
the CUNY School of Medicine shows that drugs that increased signaling
by a protein called sonic hedgehog, or Shh, can inhibit LID. Such a
treatment would have the potential to help most Parkinson's patients,
the authors said.

The study appears in Communications Biology.

"In rodent and non-human primate models, the administration of L-dopa
together with sonic hedgehog agonists attenuate the expression of LID,"
said Lauren Malave, Ph.D., first author and postdoctoral fellow at
Columbia University, previously a Ph.D. student in the lab of Professor
Andreas Kottmann, Ph.D., at the CUNY School of Medicine at City College
of New York and the Graduate Center. "We provide novel insight into
the underlying mechanisms behind LID formation and provide a potential therapeutic solution." Parkinson's disease is caused by the death of
dopamine neurons, which is why the disease is treated with medications
that are converted to dopamine once they enter the body. Key to the
new study, though, is that these neurons also produce neurotransmitters
other than dopamine, including GABA, glutamate, and Shh.

Shh has not previously been considered a neurotransmitter, but the new
paper shows that it does in fact act as a neuromodulator. The researchers
found that dopamine neurons use Shh to communicate with cholinergic
neurons, which scientists have thought might play a role in LID. They
then used animal models of Parkinson's disease to show that decreased
Shh signaling in the basal ganglia, caused by death of dopamine neurons, facilitates LID. On the other hand, mimicking increased signaling by
Shh reduced LID. Because of this, the authors suggest that the imbalance between dopamine and Shh after L-dopa treatment is a major cause of LID.

The next steps will be to develop new therapeutics that act downstream
in the Shh pathway in cholinergic neurons and begin clinical trials.

"Deep brain stimulation doesn't help everyone, it's very invasive,
and not all people are eligible for the surgery. The procedure is also
not accessible to everyone," said Kottmann, who was the corresponding
author on the paper. "What we find in this study is that in several
animal models, by replacing not only dopamine but dopamine together with agonists that mimic the effects of sonic hedgehog, these dyskinesias can
be very much suppressed." This research was supported by the American Parkinson Disease Association and the National Institutes of Health and
the Research Foundation of the City University of New York.

========================================================================== Story Source: Materials provided by The_Graduate_Center,_CUNY. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Lauren Malave, Dustin R. Zuelke, Santiago Uribe-Cano, Lev Starikov,
Heike
Rebholz, Eitan Friedman, Chuan Qin, Qin Li, Erwan Bezard, Andreas H.

Kottmann. Dopaminergic co-transmission with sonic hedgehog inhibits
abnormal involuntary movements in models of Parkinson's disease
and L- Dopa induced dyskinesia. Communications Biology, 2021; 4
(1) DOI: 10.1038/s42003-021-02567-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210922090843.htm

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