Reconstructing the brain: approaches to treating Parkinson’s disease

Image: Torpor and Parmar, Lund University
Image: Torpor and Parmar, Lund University

Dr Malin Parmar and colleagues concisely describe in an ACNR review efforts over the past 30 years to develop a treatment for Parkinson’s disease patients that replaces destroyed nerve cells in the brain. Many different approaches are being taken, from brain cell transplants to using pluripotent stem cells. Now, a technology called ‘direct neural conversion’ can be added to the arsenal of tools researchers are using.Image removed.

Dr Torper, Dr Parmar and colleagues recently published an article in Cell Reports showing that their method of ‘direct neural conversion’ creates new neurons in the brains of mice that integrate and signal with neurons already in the brain. These results suggest that direct neural conversion may be a valuable tool for developing future treatments to replace neurons lost by patients with Parkinson’s disease and other diseases that destroy neurons.  

What is the idea behind the review and study?

Roughly 10 million people worldwide suffer from Parkinson’s disease (PD). This disease causes neurons in the area of the brain called the ‘substantia nigra’ to die, which leads to symptoms of tremors (shaking), slow movements, and muscle stiffness. Presently there are no medical treatments that halt or fix the problems causing PD, but researchers are working to change this. The review discusses technologies that are being developed for replacing neurons lost in a PD patient’s brain. The hope is that these technologies may become treatments for restoring brain function in Parkinson's disease patients. 

What does the review and study discuss?

In 1987 researchers in Lund, Sweden were the first to attempt replacing neurons destroyed by PD in two patients' brains using a method called a ‘foetal cell transplant’. These two patients showed substantial improvements prompting more clinical trials around the globe. However, the trials had very mixed results. Researchers have since studied the results of these different transplants to design the present TRANSEURO project, a new phase 1 clinical trial funded by the European Union.

Although foetal brain cell transplants are a promising treatment for PD, they carry several ethical and technical problems. Ethical issues over using aborted foetuses for medical and research purposes are widely debated. This aside, the availability of foetal brain cells and standardising the quality of these cells in each treatment (cells from different foetuses may behave differently) are two big obstacles to making the treatment widely available. Dr Parmar and colleagues point out in their short review that renewable and abundant sources of cells that do not rely on foetuses are ‘an absolute necessity’.

Pluripotent stem cells are the primary alternative source of cells researchers are investigating for PD disease treatments because these cells can turn into any type of cell in the body, including the neurons that die in PD patients. Researchers want to use pluripotent stem cells to make the neurons PD patients need and transplant these instead of foetal brain cells. Quantities of pluripotent stem cells aren’t as limited as foetal brain cells because they can be grown in large numbers. This also means the same cells could be used for many treatments, making outcomes more predictable. However, there are different types of pluripotent stem cell and each has complications and ethical issues. Perhaps the biggest concern with all pluripotent stem cells is creating reliable methods for controlling how stem cells multiply and transform into neurons. If transplanted cells are not tightly controlled, they can begin to multiply and change into the wrong types of cells, potentially causing tumours, cancers or other problems.

Induced neurons made by Dr Torper and colleagues with their ‘direct neural conversion’ method are shown in green. These cells took 12 weeks to form after the conversion was started. The bottom image shows a single induced neuron at 5 times greater magnification (zoomed in) than the cells shown in the top image. White bars represent a length of 50 microns (top) and 10 microns (bottom).
Induced neurons made by Dr Torper and colleagues with their ‘direct neural conversion’ method are shown in green. These cells took 12 weeks to form after the conversion was started. The bottom image shows a single induced neuron at 5 times greater magnification (zoomed in) than the cells shown in the top image. White bars represent a length of 50 microns (top) and 10 microns (bottom).

A new technology called ‘direct neural conversion’ is giving researchers new ideas and options for treating diseases like PD. Direct neural conversion can turn any cell from a patient directly into a neuron. These ‘induced neurons’ potentially avoid some of the risks pluripotent stem cells have. Dr Parmar’s laboratory and several other research groups have even used this method to make new neurons inside the brains of living mice. The exciting part is that researchers are able to convert a type of brain cell already in the brain, called ‘glial cells’, into the new neurons, so no transplant is needed. Dr Parmar and colleagues show in their Cell Reports article that their direct neural conversion method creates functional neurons that receive signals and successfully integrate into the brain’s network of neurons. There’s lots of work to be done before this method will ever be tested in people, but it certainly is a new and promising approach for developing future PD treatments.

What does this mean for patients?

This review and original research article by Dr Parmar and colleagues primarily show that advancements are being made and new technologies may offer different approaches to treatments. In the case of foetal cell transplants, the TRANSEURO project clinical trial holds promise. The study and analysis of the results will take several years, but if it goes well there may be a clinically proven treatment for PD available. This will not mean it’s widely available, however. This treatment will also prompt lots of ethical debates about government rules and regulations for the treatment, which may delay its availability too. That’s why researchers are still looking for other alternatives. Different forms of pluripotent stem cells and new methods, such as direct neural conversion, offer great promise for developing future regenerative medicines for Parkinson’s disease, but these technologies will take time.

Further information and links

This ‘Research Spotlight’ is based on the review ‘Cell therapies for Parkinson’s disease’ by Malin Parmar et al., 2014 ACNR 14(3):26-8 and original research article In Vivo Reprogramming of Striatal NG2 Glia into Functional Neurons that Integrate into Local Host Circuitry by Torper et al., 2015 Cell Reports 12(3): 474-481. A journal subscription may be required for access to these articles.

A very good ‘reader friendly’ description of the ‘direct neural conversion’ method can be found on National Geographic’s website blog ‘Phenomena’. This 2013 blog article describes an earlier research publication, before Dr Parmar’s laboratory showed that the new neurons created integrate with neurons already in the brain.

Related content:

Information on Parkinson’s disease:

Additional information on current treatments and treatments being developed for Parkinson’s disease:

  • TRANSEURO, a research collaboration and clinical trial program
  • GForce-PD, a global network to bring cell therapies to PD patients 
  • Parkinson’s UK has general information and also lists clinical trials for people with Parkinson’s disease

Acknowledgements

Written by Ryan Lewis, edited by Jan Barfoot, reviewed by Malin Parmar. Images of neurons were provided by Dr Torper.

Details about the picture in this article

Induced neurons made by Dr Torper and colleagues with their ‘direct neural conversion’ method are shown in green. These cells took 12 weeks to form after the conversion was started. The bottom image shows a single induced neuron at 5 times greater magnification (zoomed in) than the cells shown in the top image. White bars represent a length of 50 microns (top) and 10 microns (bottom). 


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