FIGURE 4.

Schematic representing possible mechanisms underlying POLR3-HLD. In wild-type conditions (healthy individuals), Pol III synthesizes small ncRNAs that play essential roles in housekeeping processes such as translation and co-translational targeting of nascent peptides, which are necessary for the production of myelin. In individuals with POLR3-HLD, it is hypothesized that mutations in Pol III subunits (POLR3A, POLR3B, POLR1C or POLR3K) result in reduced Pol III transcription and decreased levels of Pol III transcripts. The “tRNA-centric” hypothesis postulates that lower levels of tRNAs (either globally, for specific anticodons or for specific isodecoders) will impact translation and synthesis of proteins that are essential for myelination. Alternatively or in addition, reduced levels of other Pol III transcripts may contribute to POLR3-HLD pathogenesis through suboptimal performance of their respective functions that will particularly affect oligodendrocytes and/or neurons. An example is shown for 7SL RNA, where reduced levels of this ncRNA could impair translocation of secreted or transmembrane proteins to the ER, which could impact production of myelin. The schematic of the neuron was adapted from images available on https://smart.servier.com.