People who develop Parkinson's disease before the age of 50 may have been born with already damaged brain cells that have gone undetected for decades.
Scientists at the Institute of Regenerative Medicine at Cedars-Sinai Medical Center, in an article published in Nature Medicine, argue that early Parkinson's is possibly a congenital disorder.
This neurodegenerative disorder usually affects older people, and symptoms develop rather slowly. In parkinsonism, the dopamine-producing neurons in the brain are damaged and killed. Dopamine also determines the ability to coordinate muscle movements, which determines the well-known symptoms of the disease: slowness, muscle stiffness, tremors and loss of balance. In most cases, the exact cause of neuronal failure is unclear, and there is no known cure for the underlying cause - only symptom relief.
Although most patients are 60 or older at the time of diagnosis, about 10% of patients are younger: 21 to 50 years old. The new study focuses specifically on these young patients.
The team grew special stem cells, known as induced pluripotent stem cells (iPSCs), from the tissues of young patients with Parkinson's disease. A special process allows the creation of incompletely differentiated cells from adult cells. These iPSCs can then produce any type of human body cell that is genetically identical to the patient's own cells. The team used iPSCs to obtain dopamine neurons from each patient, and then cultured them in vitro and analyzed the function of the neurons.
“Our technique gave us a 'window into the past' to see how well dopamine neurons were able to function from the very beginning of a patient's life,” explains senior author Dr. Clive Svendsen.
Thus, the researchers discovered two key abnormalities in dopamine neurons: the accumulation of the protein alpha-synuclein, which occurs in most forms of Parkinson's disease, and the malfunctioning of lysosomes - cellular structures that act as "garbage cans" for cells to get rid of excess proteins.
Apparently, the first is a direct consequence of the second.
“What we see with this new model is the very first signs of Parkinson's disease. It looks like the dopamine neurons in these people can continue to mal-process alpha-synuclein for 20 or 30 years, causing Parkinson's symptoms,”explains Svendsen.
The authors of the work hope that the model of disease development they built with the help of iPSCs can help when testing a number of drugs. If the calculations turn out to be correct, the disorders caused by the disease could be “fixed”.
Scientists found that an already existing and approved active ingredient for the treatment of precancerous skin conditions - PEP005 - reduced the level of alpha-synuclein both in dopamine neurons in vitro and in laboratory mice.
The drug also counteracted another abnormality that the authors found in the dopamine neurons of patients - an increase in the level of an active version of an enzyme called protein kinase C: however, the mechanism of how this enzyme works for the benefit of Parkinson and against the patient is not yet clear.
The next research should create an affordable form of the drug that can be taken to the stage of clinical trials in humans. While we are talking about the treatment or prevention of Parkinson's disease in young patients, but in the future, scientists will test how their findings are applicable to other forms of the disease.