Transforming Brain Cells to Replace Dopamine
Monday, 20th July 2020

Star-shaped cells called astrocytes perform many duties in the brain, but their latest trick could replace dopamine cells lost in Parkinson’s disease.

Two research groups have recently published that they could turn astrocytes into dopamine cells in the brains of Parkinson’s models, which helped regain some movement ability. While there is much work to do to understand the potential of this approach in humans, these findings present a new way to approach replacing the dopamine lost in Parkinson’s and helping maintain or restore motor function.

Dismantling the “Off” Switch

Astrocytes play supportive roles in transmission of electrical signals and provision of nutrients in the brain, among other functions. Astrocytes and neurons —nerve cells that transmit information — arise from the same type of cell during development. There is a mechanism, though, that prevents astrocytes from becoming neurons.

“What these authors discovered is that blocking a single protein, polypyrimidine tract-binding protein 1, or PTB, disables that mechanism and allows astrocytes to realize their neuronal fate,” says Brian Fiske, PhD, Michael J. Fox Foundation (MJFF) Senior Vice President of Research Programs.

In parallel studies using different methods, scientists from the University of California, San Diego and from the Shanghai Research Center for Brain Science and Brain-Inspired Intelligence cut off activity of the gene that makes the PTB protein to lower its levels. Both saw astrocytes convert to dopamine neurons and the disease models improve on tests of motor function.

Fiske points out that while cell-conversion strategies are not new, targeting PTB is novel and may be a quicker route to replace cells lost in PD and boost dopamine. In addition, unlike replacement using stem cells or other sources, astrocyte conversion utilizes the body’s own cells, circumventing some of the challenges associated with introducing foreign cells.

Improving Aspects of Disease

Converting astrocytes into neurons joins a list of other approaches to cell replacement and regeneration with a goal of restoring dopamine in the Parkinson’s brain. Trials in Australia and Japan are testing the implantation of dopamine neurons engineered from stem cells. (MJFF funded early work that allowed scientists to make dopamine cells from stem cells.) Other groups are using gene therapy to help the brain boost its dopamine production, including a program whose early development was supported by MJFF.

These strategies are promising in helping to regain dopamine and motor function — perhaps easing tremor, slowness and stiffness — but scientists and patients know Parkinson’s disease is more than loss of dopamine and movement problems. Other pathology is at play, such as accumulation of the protein alpha-synuclein in cells, and there are other complex symptoms such as cognitive issues and mood changes.

“If it works, it could restore some dopamine function and the motor control aspects of Parkinson’s, which is an important goal as movement issues affect quality of life. But in its current design, a therapy like this wouldn’t necessarily stop what’s happening in other parts of the brain and the body,” Fiske says.

Testing for Answers

Each finding brings new questions. These recent papers show a promising approach to replace dopamine, but there are many more steps in its development. Some questions scientists are asking:

  • Will this work in humans? The step from models to humans is where many therapies fail because we are more complex animals. Next, scientists will need to replicate their results in other Parkinson’s models to mimic the human disease more closely.
  • Is it safe? Questions remain around depleting astrocytes by turning them into neurons and around the safety of the new dopamine cells. Will they function as they should? Will they be stable over time? Longer studies may help bring answers.
  • Who would this therapy work for? Most of these studies were done in younger Parkinson’s models. One group did run the test on older models and found a less robust response in astrocyte conversion. Another area for research will be to determine who may respond to this therapy and who to enroll in trials.

Article Source: The Michael J. Fox Foundation for Parkinson’s Research

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