Aging neurons generated directly from the skin more accurately mimic Parkinson's disease

The possibility of making almost all types of human cells from induced pluripotent stem cells (iPSCs) has opened up new avenues
for building disease models in the laboratory.
iPSCs are embryo-like cells that are produced
from a patient's skin through a process called reprogramming.
One drawback of this technique, however, is that during the reprogramming process, donor-age-specific cellular signatures are erased, so cells made from iPSCs often resemble cells of human embryos or fetuses, rather than those
of adult or elderly individuals.
However, neurodegenerative diseases like Parkinson's disease (PD) primarily affect older adults, making it difficult to model with neurons derived from PSCs because PSCs lack many of the defining characteristics
of senile neurons.

In the United States, one way to preserve the aging characteristics of neurons is to extract neurons directly from the patient's skin without the use of iPSC intermediates
.
By introducing a special combination of nerve-inducing genes into skin cells, the researchers successfully turned skin cells in Parkinson's disease patients into so-called dopaminergic (DA) neurons, a type
of neuron that Parkinson's disease sufferers gradually lose.
The process of generating DA neurons directly from skin cells preserves the genetic, epigenetic, and metabolic characteristics
of donor age compared to PD cells generated from iPS cells.

Compared to elderly DA neurons from healthy skin donors, neurons in PD patients have PD-specific cell defects and can now be modeled for the first time in sporadic PD patients lacking known gene mutations
.
With this new tool, the researchers hope to model PD-related neuronal defects from a larger cohort of PD patients, with the aim of identifying the cause of the disease as well as potential future treatments
.

essay

Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson’s disease