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

NEUROBIOLOGY OF DISEASE

卷:129

Article

Booth, Heather D. E.¹  Wessely, Frank²  Connor-Robson, Natalie¹  Rinaldi, Federica³  Vowles, Jane³  Browne, Cathy³  Evetts, Samuel G.^1,4  Hu, Michele T.^1,4  Cowley, Sally A.^1,3  Webber, Caleb^1,2  Wade-Martins, Richard¹ 

[1] Univ Oxford, Oxford Parkinsons Dis Ctr, Oxford, England

[2] Cardiff Univ, UK Dementia Res Inst, Maindy Rd, Cardiff CF24 4HQ, S Glam, Wales

[3] Univ Oxford, Sir William Dunn Sch Pathol, James Martin Stem Cell Facil, Oxford, England

[4] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England

关键词: Induced pluripotent stem cells;    Astrocytes;    Neurodegeneration;    Parkinson's disease;    LRRK2;   

DOI  :  10.1016/j.nbd.2019.05.006

来源: Elsevier

【 摘 要 】

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 a-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.

【 授权许可】

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