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RNA sequencing reveals MMP2 and TGFB1 downregulation in LRRK2 G2019S Parkinson's iPSC-derived astrocytes

Booth, Heather D.E., Wessely, Frank, Connor-Robson, Natalie ORCID:, Rinaldi, Federica, Vowles, Jane, Browne, Cathy, Evetts, Samuel G., Hu, Michele T., Cowley, Sally A., Webber, Caleb ORCID: and Wade-Martins, Richard 2019. RNA sequencing reveals MMP2 and TGFB1 downregulation in LRRK2 G2019S Parkinson's iPSC-derived astrocytes. Neurobiology of Disease 129 , pp. 56-66. 10.1016/j.nbd.2019.05.006

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Non-neuronal cell types such as astrocytes can contribute to Parkinson's disease (PD) pathology. The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is one of the most common known causes of familial PD. To characterize its effect on astrocytes, we developed a protocol to produce midbrain-patterned astrocytes from human induced pluripotent stem cells (iPSCs) derived from PD LRRK2 G2019S patients and healthy controls. RNA sequencing analysis revealed the downregulation of genes involved in the extracellular matrix in PD cases. In particular, transforming growth factor beta 1 (TGFB1), which has been shown to inhibit microglial inflammatory response in a rat model of PD, and matrix metallopeptidase 2 (MMP2), which has been shown to degrade α-synuclein aggregates, were found to be down-regulated in LRRK2 G2019S astrocytes. Our findings suggest that midbrain astrocytes carrying the LRRK2 G2019S mutation may have reduced neuroprotective capacity and may contribute to the development of PD pathology.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: Described as an Open Access article Attribution 4.0 International (CC BY 4.0) on website
Publisher: Elsevier
ISSN: 0969-9961
Date of First Compliant Deposit: 18 June 2019
Date of Acceptance: 10 May 2019
Last Modified: 03 May 2023 12:13

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