Presentation

Question 1

SVA insertion in TAF1 causes XDP

Answer 1

To quickly recap what we learned in the lecture, XDP is thought to be caused by the insertion of an SVA in intron 32 of the TAF1 gene

This results in expression of intron 32, a truncated transcript and decreased expression of exons 32-38

This SVA activity is suppressed by Zinc finger 91

Question 2

Does TAF1 dysregulation cause XDP?

Answer 2

With increasing i32 expression, canonical TAF1 expression decreases

Mice with viral deletion of TAF1 at P21 showed motor dysfunction, which was attributed to a loss of purkinje cells of the cerebellum
Not in line with symptoms, striatum not measured

However, mice with a viral knockdown of TAF at P21, more accurate model showed no differences in purkinje cells, downregulation of transcripts associated with glutamatergic, cholinergic signalling and others associated with striatal dysfunction

Corresponding to a loss in striatal cholinergic neurons
Balance with DA neurons in striatum
Similar to dystonia and huntingtons, a disease which shows a lot of pathological similarities with XDP

Question 3

Hexameric repeat length predicts age of onset

Answer 3

The repeat number of the hexameric repeat at the end of the SVA inversely correlates with both the age of onset and the TAF1 gene expression

Since TAF1 expression declines over age in the striatum naturally, the expression may drop below a certain pathological threshold faster if there is a reduction in development

What could the molecular mechanisms behind this be?

Question 4

HR and AO: G-Quadruplex hypothesis

Answer 4

The plus strand of the SVA is rich in guanine nucleotides, and is predicted in-silico to contain these G-Quadruplex tertiary structures

These structures in DNA have been shown to reduce transcription and their unwinding to increase transcription

Longer repeats may induce more of these structures, interrupting transcription and leading to lower TAF1 levels during development