People who develop Parkinson’s
disease before age 50 may have been born with disordered brain cells that went
undetected for decades, according to new Cedars-Sinai research. The research
points to a drug that potentially might help correct these disease processes.
Parkinson’s occurs when brain
neurons that make dopamine, a substance that helps coordinate muscle movement,
become impaired or die. Symptoms, which get worse over time, include slowness
of movement, rigid muscles, tremors and loss of balance. In most cases, the
exact cause of neuron failure is unclear, and there is no known cure.
At least
500,000 people in the U.S. are diagnosed with Parkinson’s each year, and the
incidence is rising. Although most patients are 60 or older when they are
diagnosed, about 10% are between 21 and 50 years old. The new study, published
in the journal Nature Medicine, focuses on these
young-onset patients.
“Young-onset Parkinson’s is
especially heartbreaking because it strikes people at the prime of life,” said
Michele Tagliati, MD, director of the Movement Disorders Program, vice chair
and professor in the Department of Neurology at Cedars-Sinai. “This exciting
new research provides hope that one day we may be able to detect and take early
action to prevent this disease in at-risk individuals.” Tagliati was a
co-author of the study.
To perform the study, the research
team generated special stem cells, known as induced pluripotent stem cells
(iPSCs), from cells of patients with young-onset Parkinson’s disease. This
process involves taking adult blood cells “back in time” to a primitive
embryonic state. These iPSCs can then produce any cell type of the human body,
all genetically identical to the patient’s own cells. The team used the iPSCs
to produce dopamine neurons from each patient and then cultured them in a dish
and analyzed the neurons’ functions.
“Our technique gave us a window back
in time to see how well the dopamine neurons might have functioned from the
very start of a patient’s life,” said Clive Svendsen, PhD, director of the
Cedars-Sinai Board of Governors Regenerative Medicine Institute and professor
of Biomedical Sciences and Medicine at Cedars-Sinai. He was the study’s senior
author.
The researchers detected two key
abnormalities in the dopamine neurons in the dish:
·
Accumulation of a protein called alpha-synuclein,
which occurs in most forms of Parkinson’s disease.
·
Malfunctioning lysosomes, cell structures that act as
“trash cans” for the cell to break down and dispose of proteins. This
malfunction could cause alpha-synuclein to build up.
“What we are seeing using this new
model are the very first signs of young-onset Parkinson’s,” said Svendsen. “It
appears that dopamine neurons in these individuals may continue to mishandle alpha-synuclein
over a period of 20 or 30 years, causing Parkinson’s symptoms to emerge.”
The investigators also used their
iPSC model to test a number of drugs that might reverse the abnormalities they
had observed. They found that that one drug, PEP005, which is already approved
by the Food and Drug Administration for treating precancers of the skin,
reduced the elevated levels of alpha-synuclein in both the dopamine neurons in
the dish and in laboratory mice.
The drug also countered another
abnormality they found in the patients’ dopamine neurons — elevated levels of
an active version of an enzyme called protein kinase C — although the role of
this enzyme version in Parkinson’s is not clear.
For the next steps, Tagliati said
the team plans to investigate how PEP005, currently available in gel form,
might be delivered to the brain to potentially treat or prevent young-onset
Parkinson’s. The team also plans more research to determine whether the
abnormalities the study found in neurons of young-onset Parkinson’s patients
also exist in other forms of Parkinson’s.
“This research is an outstanding
example of how physicians and investigators from different disciplines join
forces to produce translational science with the potential to help patients,”
said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs and
dean of the Medical Faculty at Cedars-Sinai. “This important work is made
possible by the dual leadership of Cedars-Sinai as both a distinguished
academic institution and an outstanding hospital.”
Journal
article: https://www.nature.com/articles/s41591-019-0739-1
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