Objective: To study the expression of TAF1 and its isoforms in different endogenous models of X-linked dystonia-parkinsonism (XDP).

Background: The putative gene causing XDP, the TATA box-binding protein-Associated Factor gene (TAF1), is extensively alternatively spliced. A neuronal isoform (nTAF1) is said to be underexpressed in XDP brains; another splice variant (d4) carries the only transcribed genetic change associated with the disease. A large retrotransposon insertion in intron 32 of the TAF1 gene is found in all XDP patients identified to date.

Methods: RNA from blood, fibroblast cell cultures, induced pluripotent stem cell (iPSC) lines, and neurons differentiated from iPSCs (cortical and striatal), were subjected to either quantitative PCR or microarray-based gene expression experiments, to quantify the expression of TAF1, nTAF1 and d4. Additionally, CRISPR/Cas9 gene editing techniques were used to “cut-out” the insertion in intron 32 of TAF1 in iPSC. The expression of TAF1 was compared in successfully edited colonies and their isogenic controls.

Results: Canonical TAF1 transcripts were underexpressed in the XDP group in fibroblast- and in blood-derived RNA (p<0.05, microarray-based and qPCR-based experiments), as well as in the iPSC lines, and in both cortical and striatal neuronal models (ns). nTAF1 was almost undetectable in RNA derived from fibroblasts, blood, and iPSCs, and was measureable and tended to be underexpressed in XDP cortical and striatal neuron models. Transcript d4 was minimally expressed in all tissues. iPSCs successfully edited using CRISPR/Cas9 and thus without the insertion in intron 32 showed higher expression of TAF1 (canonical) compared to their isogenic controls (p=0.01).

Conclusions: Although the exact molecular mechanism is still unclarified, expression studies in different endogenous models of XDP converge on altered expression of canonical TAF1 transcripts and some of its isoforms as an important molecular phenotype of the disorder. Preliminary data support the involvement of a retrotransposon insertion in intron 32 in dysregulated TAF1 transcripts.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/taf1-and-its-isoforms-is-underexpressed-in-different-endogenous-models-of-x-linked-dystonia-parkinsonism/