As many as 4 million people are diagnosed with Parkinson's disease worldwide – around 15% before the age of 50. This serious chronic condition is triggered by a brain chemical (dopamine) imbalance affecting movement. Changes in the cells of the substantia nigra – the area of the brain that produces dopamine – are to blame. Theories for how these changes occur include, among others, accelerated ageing, environmental factors, and genetic susceptibility. Now, as reported in the January issue of Cell, scientists have taken an important step towards stem cell therapy of this disorder.
|Picture accompanying the article ‘A New Cell Model for Parkinson's Disease', PLoS Biol 2(11): e385|
© PLoS Biology 2004
Researchers at the Karolinska Institute in Sweden discovered something called a “master determinant” in the transformation of mouse embryonic stem cells into bona fide dopamine neurons, brain cells that degenerate in patients with Parkinson's disease. The findings show promise in future cell replacement therapy for this incurable condition sometimes described as ‘shaking palsy', say the study's senior authors, Johan Ericson and Thomas Perlmann.
“The use of cell replacement therapy in the treatment of Parkinson's disease is fraught with … problems,” Perlmann said in a statement. “However, clinical trials have provided important proof of principle that transplantation of dopamine neurons might work in patients.”
“Ethical and practical issues associated with transplantation of foetal dopamine neurons to patients with Parkinson's disease have triggered intense interest in the [possible] use of in vitro-engineered stem cells as an unlimited cellular source for transplantation,” Ericson says. So, the scientists set out to establish whether dopamine neurons could be generated artificially from stem cells. For this, they studied the genes expressed by the dopamine progenitor cells in the developing midbrains of embryonic mice.
The team discovered that two transcription-factor proteins, called Lmx1a and Msx1, are expressed in dopamine progenitor cells. Further analysis revealed that Lmx1 alone is able to provoke dopamine neuron generation in lab animal embryos. The authors also found that Lmx1a's early behaviour actually triggers Msx1 activity, which leads to other events known to be important in the differentiation of these nerve cells. Importantly, they also observed that Lmx1a can induce dopamine neurons when expressed in stem cells, a finding that could one day potentially lead to therapeutic dopamine neurons being generated.
The scientists are confident that these are authentic dopamine neurons. This, they stress, is critical to treating Parkinson's patients with stem cells. “[It] is of utmost importance to make the correct cell type,” says Perlmann. Complicating matters for the team, there are at least 1 000 different types of neurons in the brain, only one of which is clinically relevant to Parkinson's disease.
“Our data establish Lmx1a and Msx1 as critical intrinsic dopamine-neuron determinants, in vivo, and suggest that they may be essential tools in cell replacement strategies in Parkinson's disease,” the researchers conclude.
Further study will show whether stem cell-derived neurons will work in treating rats with Parkinson's disease. And follow-up tests will establish whether these findings in animals will hold for humans as well. The authors of the Cell paper acknowledge their contributors and funding organisations, which include the Swedish National Research Council, the Michael J Fox Foundation – set up by the American actor who suffers from Parkinson's – and the European Community through network funding and a Fifth Framework Programme (FP5) project grant.
The recently concluded three-year EU research project, called Brainstem Genetics, investigated the genetic component in brainstem development and function. Consortium scientists from Norway, Sweden, France and the UK, including those from the Karolinska Institute's department of cell and molecular biology, looked into how the brain stem regulates vital functions involved in major chronic health problems, from sleep and mood disorders through to serious conditions, such as neurodegenerative conditions and tumours.
Cell, Karolinska Institute