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. 2023 Mar 14;146(8):3513–3527. doi: 10.1093/brain/awad086

Figure 7.

Figure 7

The cartoon illustrates the suggested cascade of events in cells expressing POLR1A T642N based on the in vitro studies. The steps in the cascade are labelled 1 to 7. 1. RNA polymerase I with the mutated POLR1A subunit produces rRNA precursors that will undergo abnormal processing and 2. impaired rRNA degradation, which was documented by altered levels of mature and immature rRNA species, and their polyadenylated forms, in fibroblasts from Patient 1 compared to controls. 3. Abnormal rRNA mature species will possibly lead to abnormal ribosome biogenesis. 4. This in turn will cause nucleolar stress and defective translation. The nucleolar stress was documented in fibroblasts from Patient 1 by the presence of a reduced number of nucleoli per cell, which also were enlarged. 5. Defective translation was probably the cause of ER stress induction. 6. ER stress dysregulated the UPR pathways. In fact, protein levels of several UPR pathway components were found to be significantly different in cells from Patient 1 compared to the controls, both in resting condition and after thapsigargin-induced ER stress.