Parkinson disease treatment break through – using stem cells to develop dopaminergic neurons.

The first transplantation of stem cells in patients with Parkinson’s disease is almost within reach. However, it remains a challenge for researchers to control stem cells accurately in the lab in order to achieve successful and functional stem cell therapies for patients.

“In our preclinical assessments of stem cell-derived dopamine neurons we noticed that the outcome in animal models varied dramatically, even though the cells were very similar at the time of transplantation. This has been frustrating and puzzling, and has significantly delayed the establishment of clinical cell production protocols”, says Malin Parmar, who led the study conducted at Lund University as part of the EU network NeuroStemcellRepair.

The Lund experiments use modern global gene expression studies to better understand the path from a stem cell to a dopamine neuron. The data has been generated in close collaboration with a team of scientists at Karolinska Institute lead by Professor Thomas Perlmann, and is closely linked with a second study from the same cluster of scientists. The second study sheds new light on how dopamine neurons are formed during development, and what makes them different from other similar and neighbouring neurons.

This new insight has enabled a streamlined differentiation process resulting in pure populations of dopamine neurons of high quality.

We have identified a specific set of markers that correlate with high dopaminergic yield and graft function after transplantation in animal models of Parkinson’s disease. Guided by this information, we have developed a better and more accurate methods for producing dopamine cells for clinical use in a reproducible way, says first author Agnete Kirkeby.

The new results, published in two back-to-back articles in the leading journal in the field, Cell Stem Cell, propel stem cell therapy for Parkinson’s disease towards clinical application. The first transplants are expected to be only a few years away.

Citations:
1. Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson’s Disease. Authors: Agnete Kirkeby, Sara Nolbrant,  Katarina Tiklova, Andreas Heuer, Nigel Kee, Tiago Cardoso1, Daniella Rylander Ottosson, Mariah J. Lelos, Pedro Rifes, Stephen B. Dunnett, Shane Grealish1, Thomas Perlmann, Malin Parmar.
DOI: http://dx.doi.org/10.1016/j.stem.2016.09.004
Journal: Cell Stem Cell

2. Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages. Authors: Nigel Kee, Nikolaos Volakakis, Agnete Kirkeby, Lina Dahl, Helena Storvall, Sara Nolbrant, Laura Lahti, Åsa K. Björklund, Linda Gillberg, Eliza Joodmardi, Rickard Sandberg, Malin Parmar, Thomas Perlmann.
DOI:  http://dx.doi.org/10.1016/j.stem.2016.10.003
Journal: Cell Stem Cell

Adapted from press release from Lund University 

Study demonstrates role of gut bacteria in neurodegenerative diseases

Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are all characterized by clumped, misfolded proteins and inflammation in the brain. In more than 90 percent of cases, physicians and scientists do not know what causes these processes to occur.

Robert P. Friedland, M.D., the Mason C. and Mary D. Rudd Endowed Chair and Professor of Neurology at the University of Louisville School of Medicine, and a team of researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid that have structural similarity to brain proteins leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS. This research is published online Oct. 6 in Scientific Reports, a journal of the Nature Publishing Group.

Alpha-synuclein (AS) is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Friedland has hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. He also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain.

The research, which was supported by The Michael J. Fox Foundation, involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of AS in the intestines and the brain and increased cerebral AS aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of AS aggregates, compared with nematodes not exposed to the bacterial amyloid. A research group led by neuroscientist Shu G. Chen, Ph.D., of Case Western Reserve University, performed this collaborative study.

This new understanding of the potential role of gut bacteria in neurodegeneration could bring researchers closer to uncovering the factors responsible for initiating these diseases and ultimately developing preventive and therapeutic measures.

“These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer’s disease, Parkinson’s disease and ALS,” Friedland said. “This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut.”

This work supports recent studies indicating that the microbiota may have a role in disease processes in age-related brain degenerations. It is part of Friedland’s ongoing research on the relationship between the microbiota and age-related brain disorders, which involves collaborations with researchers in Ireland and Japan.

“We are pursuing studies in humans and animals to further evaluate the mechanisms of the effects we have observed and are exploring the potential for the development of preventive and therapeutic strategies,” Friedland said.

Publication: Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans.
doi:10.1038/srep34477
Study demonstrates role of gut bacteria in neurodegenerative diseases