In the brain, Parkinson’s is characterized by damage to dopaminergic neurons and accumulation of clumps of the protein α-synuclein. However, growing evidence indicates that other types of cells, including astrocytes, may contribute significantly to how Parkinson's progresses.
Astrocytes are the most common type of cell in the central nervous system. They play a crucial role in the development and maintenance of the neurons that they support.
We have developed a method to produce the type of astrocytes found in the mid-brain from stem cells reprogrammed using skin samples donated by people with Parkinson’s who carry LRRK2 mutations to compare to heathy controls. Such mutations in the LRRK2 gene are the most common genetic cause of Parkinson's.
Experiments were performed that measured the expression levels of all genes within these astrocyte cells. We were interested in those genes whose expression levels are different in astrocytes derived from people with Parkinson's compared to those from healthy controls. The majority of genes found to be different are involved in the extracellular matrix, which is the space between cells that is essential for their communication. In particular, two of those genes with lower expression levels in the Parkinson’s group highlight a potential role of astrocytes in the development of Parkinson’s.
The first gene called MMP2 (matrix metallopeptidase 2) produces a protein that is involved in the breakdown of other proteins, including α-synuclein clumps. Having less MMP2 can contribute to an increased burden of toxic α-synuclein in the brains of people with Parkinson’s.
The second gene called TGFB1 (transforming growth factor beta 1) produces a protein that has previously been shown to reduce inflammatory responses observed in Parkinson’s models. Lower amounts of TGFB1 produced by midbrain astrocytes may therefore point to damaged regulation of inflammatory responses in the brains of LRRK2 G2019S carriers.
Overall, we propose that midbrain astrocytes of people with this common mutation have a reduced ability to support and protect the vulnerable dopaminergic neurons from critical damage.
Read the orginal research article: Booth HDE, Wessely F, Connor-Robson N, Rinaldi F, Vowles J, Browne C, Evetts SG, Hu MT, Cowley SA, Webber C, Wade-Martins R. (2019) RNA sequencing reveals MMP2 and TGFB1 downregulation in LRRK2 G2019S Parkinson's iPSC-derived astrocytes. Neurobiol Dis. 129:56-66. PMID:31085228
Highlights from research paper
- Genome-wide RNA sequencing profiling of LRRK2 G2019S iPSC-derived astrocytes.
- The extracellular matrix is perturbed in LRRK2 G2019S iPSC-astrocytes.
- MMP2 and TGFB1 are down-regulated in the presence of the LRRK2 G2019S mutation.
- Reduced neuroprotective potential of astrocytes may contribute to PD pathology.