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Single cell sequencing found key regulators of Parkinson disease
Update time:2019-09-05 00:54:06   【 Font: Large  Medium Small

Parkinson's disease (PD) is a common degenerative disease of the nervous system, and its clinical symptoms are mainly characterized by rigidity and tremor. Currently, approximately 6 million people worldwide suffer from Parkinson's disease.
The researchers from Oxford used high-resolution, single-cell transcriptomic analyses of iPSC-derived dopamine neurons carrying the GBA-N370S PD risk variant, they identified a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Pseudotime analysis of genes differentially expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with HDAC4-modulating compounds upregulated genes early in the DE axis and corrected PD-related cellular phenotypes.Our study demonstrates how single-cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.
They also added that many of the differentially expressed genes were down-regulated by histone deacetylase 4 (HDAC4), suggesting that targeting it may affect disease processes. They found that HDAC4 is incorrectly localized on the nucleus of patient iPSC-differentiated dopamine neurons, inhibiting gene expression at an early stage, leading to defects in late protein balance.
The researchers then used four compounds that target HDAC4 to treat dopamine neurons in patients. They reported that these compounds reversed the decline in expression of early disease-associated genes, and that further processing later limited the expression of endoplasmic reticulum stress genes.
"We found that the disease process is a dynamic event and determined that HDAC4 is a key regulator of early molecular changes that lead to advanced pathological processes," the authors said.
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