Huntington’s disease(HD) is a fatal genetic disorder, more common among people of Western Europe, that leads to the decline of one’s muscle coordination as well as cognitive faculty. One of the major causes behind involuntary and erratic writhing movements of hands and feet, called chorea, this neurodegenerative disease usually makes itself visible at middle-adulthood, between 35 to 44 years of age. Following the first appearance of symptoms, the patients generally live for another 20 years. While the medical world is still grappling for a cure, researchers at St. Louis-based Washington University School of Medicine have devised a method by which human skin cells can be directly converted in a specific kind of brain cell, attacked by Huntington’s.
The breakthrough takes a different route from the complicated and extensive process of reverting the patient’s own cells to the pluripotent stem cell stage. Instead, the conversion, in this case, takes place in one simple step, thus eliminating the need to produce multiple cell types. The brain cells in question are the medium spiny neurons, also called spiny projection neurons, that inhabit the corpus striatum of the basal ganglia. Responsible for the control and coordination of various movements of the body, including the limbs and the eyes, these specialized cells are the first to be affected by Huntington’s disease.
The team, headed by senior author and assistant professor Andrew S. Yoo, chose adult human skin cells, instead of the more commonly used mouse cells or other incompletely developed human cells, because they are indeed abundantly available. Furthermore, these cells, sourced from the patient’s own body, are readily accepted by the immune system. Earlier studies have shown that two specific types of RNA molecules are capable of reprogramming the common skin cells into a variety of neurons. Based on this knowledge, Yoo and his colleagues placed the skin cells in a environment that is somewhat similar to the environment of brain cells.
Consequently, exposure to two types of microRNAs, in this case miR-9 and miR-124, resulted in a change in the machinery that controls DNA packaging of the particular skin cells. Although the process is not completely understood, Yoo and the others believe that the microRNAs help unravel the specific DNA information, associated with brain cells, leading to the expression of genes responsible for the development of neurons.
In order to facilitate the process of conversion of the cells into medium spiny neurons, the researchers fine-tuned the neurological and chemical signals, by exposing the skin cells to specific types of proteins called transcription factors. Found in the section of the brain where spiny projection neurons are usually present, these transcription factors help govern the rate of transfer of genetic information from the DNA strands to the corresponding mRNAs. Talking about the study, published in the journal Neuron, Matheus B. Victor, co-lead author and graduate student of neuroscience, said:
We think that the microRNAs are really doing the heavy lifting… They are priming the skin cells to become neurons. The transcription factors we add then guide the skin cells to become a specific subtype, in this case medium spiny neurons. We think we could produce different types of neurons by switching out different transcription factors.
According to Yoo, however, the constituent microRNAs form the crucial components of the experiment, as merely exposing the human skin cells to transcription factors, without microRNA molecules, failed to successfully transform them into functional neurons. Additional observations showed that artificially converted brain cells survived for at least six months, after being transplanted into the mouse brain, and behaved almost exactly like the original medium spiny neurons. They were also found to possess morphological and functional properties, as well as genetic information, similar to that of the native neurons. Yoo said jubilantly:
Not only did these transplanted cells survive in the mouse brain, they showed functional properties similar to those of native cells…These cells are known to extend projections into certain brain regions. And we found the human transplanted cells also connected to these distant targets in the mouse brain. That’s a landmark point about this paper.
The next step for the scientists is to investigate the effect these artificially-converted neurons have on the individual symptoms, when injected into the brains of mice suffering from a model of Huntington’s chorea. If successful, the research can lead to the development of effective and targeted treatments for the disease.