Mucolipidosis Type IV is a rare hereditary condition which has a particularly devastating effect on the development of the nervous system, leading to mental retardation and severe impairment of motor function. As a result, most victims are unable to speak and incapable of unaided movement. The disease is also associated with progressive retinal degeneration. Mucolipidosis Type IV is characterized by abnormal intracellular accumulation of lipids and mucopolysaccharides in the specialized, membrane-delimited compartments called lysosomes, in which these biomolecules are normally degraded. This defect leads to the build-up of lipids and toxic concentrations of metal ions, which disrupt cell function and ultimately lead to cell death. The disease is caused by specific mutations in a single gene, which codes for the protein TRPML1. TRPML1 forms pores in the lysosomal membrane, through which positively charged ions can pass in a controlled fashion. “These so-called ion channels regulate the concentration of cations and the pH (H+ level) in the lysosome, and are essential for its normal function,” says LMU pharmacologist Dr. Christian Grimm. Together with members of his research group, Grimm has now identified a synthetic drug which can correct the defect in TRPML1 in cells carrying some of the mutations known to disable the function of the channel.
So far, around 20 distinct loss-of-function mutations have been pinpointed in the TRPML1 gene. “In the case of mutations that disrupt the function of the channel – but do not affect its stability or subcellular localization – it should in principle be possible to reactivate that function,” Grimm points out. “The aim of our project was to identify such mutations, and to develop synthetic compounds of low molecular weight, i.e. small molecules, that could restore channel function by binding to the mutant protein at an appropriate site.” The team has now reported the outcome of these efforts in the journal “Nature Communications”. The new results are of potential clinical relevance, as no treatment for mucolipidosis is currently available.
The researchers identified three mutant forms of the channel that were theoretically amenable to “repair” by treatment with small-molecule ligands. Grimm and his co-workers then asked whether these mutant channels could still interact with PI(3,5)P2, the natural ligand of TRPML1 which normally regulates the opening of the pore. These experiments revealed that the mutant channels no longer responded to the natural activator. “So we went on to design a synthetic binding partner, a small compound we call MK6-83,” Grimm explains. And indeed, MK6-83 was found to reactivate the function of two of the three mutant forms of the channel that are stably incorporated into the lysosome membrane in cells isolated from mucolipidosis patients bearing the corresponding mutations.
MK6-83 is therefore a promising drug candidate for the development of new approaches to the therapy of mucolipidosis Type IV. “The synthetic molecule may actually be a more potent activator than PI(3,5)P2, because it binds to a different site within the channel – which is much closer to the pore itself,” says Grimm. He and his colleagues now intend to test the effects of MK6-83 in transgenic mouse strains that carry the relevant mutations in the gene for TRPML1.