By Andrew Gao
Parkinson’s disease, a neurodegenerative disorder that kills off dopamine-producing (dopaminergic) neurons, is widely known — and feared. Unlike other prevalent illnesses such as tuberculosis and diabetes, we have yet to find an effective treatment for Parkinson’s disease.
Neurodegenerative diseases are notoriously difficult to treat due to the delicate nature and unique mechanisms of the human brain. Parkinson’s, in particular, is caused by the mass death of dopaminergic neurons in the substantia nigra, a part of the brain that controls muscle movement. Currently, doctors are able to slow down the progression of Parkinson’s disease but not reverse its course or get rid of it entirely. For decades, researchers have tried and failed to find a cure for this common, debilitating disorder. Success has been elusive.
Recent findings from a research team at the University of California, San Diego (UCSD) may be the first steps toward a cure for Parkinson’s. Led by Professor Xiang-Dong Fu and graduate student Hao Qian, the team published a groundbreaking paper on the findings of their neuron research in the prestigious journal, Nature (Qian et al.). Titled “Reversing a model of Parkinson’s disease with in situ converted nigral neurons,” the paper has amassed over 56,000 views barely five months after its June 2020 publication.
The popularity of the paper is unsurprising, given the implications of its novel strategy for treating Parkinson’s disease. While current treatment strategies focus on restoring dopamine levels or preventing the loss of dopaminergic neurons, Fu’s team took a different approach: replacing lost neurons entirely. They were able to convert astrocytes — abundant support cells in the brain — into functioning neurons using man-made strands of DNA that disable RNA (RNA are molecules that instruct cells to make proteins). The researchers focused on pyrimidine tract-binding (PTB) protein. Without working RNA, no PTB proteins can be produced. Without PTB proteins, genes can turn cells into new neurons. In neurons, there is a specific set of genes that give cells their unique properties. PTB turns off these genes. Thus, when it is removed, those genes are switched on, allowing cells to become neurons.
Mice with chemically-induced Parkinson’s disease were treated with the synthetic DNA through injection to the substantia nigra region of the brain. The mice were then observed over several months.The number of neurons in each mouse increased by an average of 30 percent. Additionally, dopamine levels increased and were similar to those of healthy mice. Just three months after the treatment, many mice regained normal motor control.
Experts are excited by the results. William Mobley, MD, PhD, a professor of neuroscience at UCSD, stated that he was “stunned at what [he] saw.” As he put it, the researchers’ innovative strategy could potentially help patients who have advanced Parkinson’s disease. The results are especially promising because they were demonstrated in vivo, that is, in living organisms — in this case, mice. Because the treatment worked in living mice, it is likely that it will also work in humans.
Despite the promise shown in the study, the lead researcher, Fu, like any responsible scientist, is quick to point out that more research is needed before claims about a cure for Parkinson’s can be made. For one, the study focused on mice, which are an imperfect model organism for humans. Differences between the mouse and human brain, from size to structure, could alter the outcome in humans. Also, the authors note that there is an age-related decline in the treatment’s effectiveness in older mice. As Parkinson’s disease mainly affects the elderly, this decrease could be problematic. While the mice reportedly saw no Parkinson's symptoms for the remainder of their lives, the human lifespan is substantially longer. Fu also notes that the treatment injection technique requires brain surgery that is “invasive and potentially dangerous” for humans.
Despite reservations, Fu comments that the findings are “proof of a concept” and “just the beginning.” As he humorously quips, “we cannot just get overexcited” and start to “shoot these things into human brains” immediately.
While Fu’s paper has generated significant buzz in the neuroscience world, similar research by scientists at the Shanghai Institute for Biological Sciences is also worthy of attention (Zhou et al.). Inspired by Fu’s success, the Chinese researchers, under the guidance of Professor Hui Yang, sought to reduce the levels of the PTB protein in astrocytes. However, instead of Fu’s method, they used a variant of the genetic editing system CRISPR-Cas9. They were also able to make neurons, validating the UCSD team’s approach. The next step, according to Yang, is to test the CRISPR treatment in non-human primates, such as chimpanzees.
The PTB Protein
While the two studies have their differences, there is one interesting similarity: the PTB protein. The protein is involved in cellular differentiation, the process by which cells gain specific functions. All cells in the human body have the same genes, yet there is great diversity in what each cell does, from helping us see to carrying brain signals. Certain genes are turned on or off in each type of cell. For example, genes involved in producing digestive enzymes would likely be turned on in stomach cells but not in skin cells. PTB protein is able to deactivate the genes that make neurons, preventing cells from becoming neurons. In the absence of PTB, those neuron-producing genes get to work.
A Stroke of Luck
PTB was known to affect genes for decades but scientists did not know that removing it could turn cells into neurons until an accidental discovery was made. A researcher in Fu’s lab was working with connective tissue cells to study the effects of PTB by reducing it. The method he was using caused only temporary PTB suppression so it had to be repeated often. Growing tired of the tedious task, the researcher decided to create cells that neglected to produce PTB. To his surprise, most of the tissue cells turned into neurons. In perhaps one of the most serendipitous moments in science, this chance experiment revealed that by eliminating just one protein, cells could be transformed into neurons.
Regardless of the circumstances of discovery, the reduction of PTB protein has tremendous promise in treating Parkinson’s disease. The treatment could likely be applied to other neurodegenerative diseases such as Alzheimer’s or even spinal cord injuries, according to Yang. While there is a long road ahead, replete with clinical trials and extensive testing, the PTB protein will certainly be a focal point of future research.
Primary Source: Interview with Professor Xiang-Dong Fu
Primary Source: Interview with Professor Hui Yang
Glia-to-Neuron Conversion by CRISPR-CasRx Alleviates Symptoms of Neurological Disease in Mice (April 2020)
Reversing a model of Parkinson’s disease with in situ converted nigral neurons