Researchers have developed a new method to generate dopamine-producing neurons from the skin cells of patients with Parkinson’s disease, a process that could be used to better study the molecular mechanisms of the disease and develop new treatments .
The cells retained many relevant aspects of disease, including alpha-synuclein accumulation, and captured age-related changes that most animal and cell models fail to recapitulate.
“Important here is that the aging signature of the donor cell is maintained during direct conversion, … which uniquely allows for the modeling of age-related aspects of” Parkinson’s disease, the researchers wrote.
The study, “Age-related pathological impairments in directly reprogrammed dopaminergic neurons from patients with idiopathic Parkinson’s disease,was published in the journal Stem Cell Reports.
Parkinson’s disease is characterized by the progressive loss of dopaminergic neurons, neurons that communicate by releasing an important chemical messenger in the brain called dopamine.
Although a feature of the disease is the accumulation of toxic clumps of alpha-synuclein inside nerve cells, the exact mechanisms leading to disease onset and development remain poorly understood. This is mainly because there is a lack of suitable models that accurately mimic disease processes.
Induced pluripotent stem cells, or iPSCs, are often used to study genetic contributions to disease. iPSCs are produced by collecting mature cells – usually cells isolated from skin samples – and reprogramming them into stem cells, which have the ability to differentiate into virtually any other type of cell in the body. in the right conditions.
When generated from an individual patient, the stem cells will carry the same disease-causing mutations as the patient. By using specific chemicals, stem cells can grow into nerve cells or other cell types of interest and then be studied in the lab.
However, as in most other models of Parkinson’s disease, one particular feature that is not captured in these cells is age, which is “the greatest risk factor for developing this disease”, the authors wrote. researchers. They also fail to retain the patient’s epigenetic characteristics, which are chemical modifications of DNA that determine which genes are read and how active they are.
Now, a team led by Swedish researchers has developed a way to generate dopaminergic neurons directly from skin cells, bypassing stem cells.
The nerve cells were obtained by treating skin cells with an optimal combination of factors necessary for the normal development and functioning of dopaminergic neurons. Analyzes of the resulting cells showed that they behaved like neurons – they could spontaneously fire electrical signals – and had increased activity of dopamine-related genes, thus determining the validity of the model.
Using the new method, the researchers generated dopaminergic neurons from 18 patients with Parkinson’s disease and 10 age- and sex-matched healthy controls. Compared to healthy controls, neurons from patients with Parkinson’s disease had impaired stress-induced autophagy, a natural recycling process in which cells break down unnecessary or damaged components.
These defects were not observed in skin cells before they were converted into neurons, confirming that the features of the disease are only seen in neurons.
Notably, neurons obtained from both healthy patients and patients with Parkinson’s disease showed characteristics related to the patient’s age. In particular, cells from older patients showed greater accumulation of lysosomes – cellular structures responsible for breaking down molecules inside cells – in their nerve cells.
The effects of the MAPT gene
This effect was more pronounced in neurons carrying a form of MAP gene associated with faster disease progression and cognitive decline. This gene provides instructions for making the Tau protein, which provides structural stability to neurons.
The patient-derived cells also showed other hallmarks of cellular aging, such as more cell damage, an age-related genetic signature consistent with the donor’s age, and accumulation of alpha-synuclein. In contrast, these age-related features were not observed in dopaminergic neurons derived from iPSCs.
“This effect of age and genetic variance on disease pathology has not been recapitulated in cellular models before, and suggests that direct conversion to [dopaminergic neurons] could be used for differential diagnosis, drug screening, and modeling of late-onset neurodegenerative diseases,” the researchers wrote.
Moreover, in neurons derived from skin cells, they detected alpha-synuclein pathology, but not in neurons derived from iPSCs. “Maintaining age in [skin cell-derived neurons] is important to model [alpha-synuclein] pathophysiology of idiopathic [Parkinson’s disease]“, they concluded.
“Future studies using this cellular model will thus contribute to a better understanding of the pathology associated with the age of [Parkinson’s disease] as well as the cellular basis of disease subtypes and variable progression and, in doing so, allow us to better develop and evaluate novel therapeutic interventions,” they added.