By Marilynn Larkin
NEW YORK (Reuters Health) - A single-step method that converts astrocytes into functional dopaminergic neurons could one day be used to treat Parkinson's and other neurodegenerative diseases, researchers suggest.
While most treatment strategies for Parkinson's aim to prevent neuronal loss or protect vulnerable neuronal circuits, "a potential alternative is to replace lost neurons to reconstruct disrupted circuits," note Dr. Xiang-Dong Fu of the University of California, San Diego and colleagues.
With this in mind, the team developed a technique to turn astrocytes into functional dopaminergic nerve cells. Astrocytes are brain cells that produce an RNA-binding protein called PTBP1, which prevents them from becoming neurons.
"We initially wished to construct a cell line in which PTB expression is reduced in order to study the functional impact on its target genes," Dr. Fu told Reuters Health by email. "Unexpectedly, such cells initially grew very slowly in culture, and soon stopped growing completely. We kept the cells in our incubator for a few weeks, wishing to obtain sufficient cells for our experiments. To our surprise, all the cells became neurons."
"We realized that something must be happing to cause such a dramatic cell fate switch," he said, "and upon testing on multiple different cell types, we found that all become neurons upon PTB down-regulation."
As reported in Nature, the team found that by downregulating PTB specifically in astrocytes, they could efficiently convert the non-neuronal cells into neurons that were able to functionally integrate into the existing neural circuits in brain.
"Interestingly," Dr. Fu said, "we also found that astrocytes in different brain regions could be reprogrammed into distinct subtypes of neurons that are closely related to the endogenous neurons in different brain areas."
The team then tested the approach in a mouse model of Parkinson's disease. "We showed that new neurons converted from astrocytes were able to replace lost dopaminergic neurons and restore dopamine levels, leading to complete reversal of the disease phenotype," Dr. Fu said.
Moreover, a similar disease reversal could be achieved by converting astrocytes to neurons using antisense oligonucleotides to transiently suppress PTB.
"Although we demonstrate this new approach in a Parkinson's disease model, the principle appears to be generally applicable to other neurological disorders," Dr. Fu noted. "This strategy would also avoid various potential complications with drafted 'foreign' cells, such as neurons derived from stem cells."
That said, he added, "We have a lot to do before initiating clinical trials on patients." For example, he said, "We need to determine the potential toxicity of our approach due to the depletion of endogenous astrocytes."
Further, "Too many new neurons or mis-targeting of new neurons may also cause some unforeseen side-effects," he said. In addition, future research needs to demonstrate that new neurons can grow in larger brains, which would require testing in non-human primates, including older animals, since most neurodegenerative diseases occur in older people.
Commenting by email, Dr. Ernest Arenas of the Karolinska Institute, author of an accompanying News and Views article, said the study "represents a major step forward towards the development of cell-replacement therapies for neurodegenerative diseases."
However, like Dr. Fu, he told Reuters Health that a number of issues need to be addressed before the approach is ready for the clinic. For example, "astrocytes were found to convert to unexpected neuronal types that connect with other neurons in the brain - a finding that requires careful investigation as it may impact on brain function in patients."
"Another important aspect to consider is that the efficiency of this method as a cell replacement approach has only been tested in mouse astrocytes and for a few months," he said. "For this strategy to reach the clinic, it will be necessary to demonstrate, in addition to safety, efficient conversion of the relevant human astrocytes in the context of disease, as well as long-term stability and functionality of the therapeutic approach for several years."
The results thus far seem comparable to other cell-replacement strategies, such as embryonic stem cell transplantation," he added. However, "the new conversion approach is simpler, as it neither requires expensive and extensive cell cultivation and banking nor does it require the use of immunosuppressive therapy to prevent cell rejection, since cells used in this strategy are in the patient's own brain."
"Thus," he concluded, "the simplicity of this approach and the broad range of potential applications make it a very attractive option for future cell replacement therapy of neurological and neurodegenerative disorders such as Parkinson's disease."
SOURCE: https://go.nature.com/2NSjciN and https://go.nature.com/2BTdGK0 Nature, online June 24, 2020.