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

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