An original and interesting observation just appeared that might help explain how the known genetic variants associated with PSP might cause the disease. It has to do with regulating gene expression.
Mariet Allen, PhD, a junior researcher at Mayo Clinic Jacksonville, and colleagues published the paper in the current issue of Acta Neuropathologica. The senior author is Nilüfer Ertekin-Taner, PhD, who received a grant from CurePSP for this work. The general idea of using such “endophenotypes” to assess the role of genetic variants in causing PSP has long been proposed by their mentor, Dennis Dickson, MD, a leading neuropathologist, who was also an author of this paper.
They used tissue from 422 brains from the CurePSP Brain Bank at Mayo that had been confirmed as having PSP. They made three types of measurements in each brain: gene expression (measured as messenger RNA), epigenetic methylation of DNA (measured as CpG islands), and numbers of the various classic PSP micro-anatomic changes that have been known for decades. They correlated those measurements with whether each case carried the major or minor allele of markers reported in the genome-wide analysis (GWAS) of single-nucleotide polymorphisms published in 2011 by Hoglinger et al. (Disclaimer: I was a minor co-author on the 2011 paper.)
Without getting too much into the details, the results were that the genetic variants and increased DNA methylation at MAPT (the gene for tau protein) and/or MOBP (the gene for myelin-associated basic protein) were associated with increased expression levels of some proteins not previously associated with PSP. One such protein was “leucine-rich repeat-containing protein 37A4” or LRRC37A, which is coded at chromosome 17q21.31-q21.32. The genetic marker status at that location was also associated with increased expression levels and methylation levels in two other proteins encoded by genes at the same approximate location, ARL17A and ARL17B. (Adenosine diphosphate ribosylation factor-like GTPases are involved in protein transcription and like LRRC37A, are located next to the MAPT gene on chromosome 17.)
LRRC37A appears to be involved in regulating interactions of proteins with other compounds. Its upregulation is known to be harmful to cells. Intriguingly, its gene produces a wide variety of alternatively spliced protein forms (where some exons’ protein products are included, others excluded, from the finished protein product) in different people and in different species. This may suggest that this gene is unstable and could easily be induced to make an inappropriate variant of its protein by a subtle exposure to a toxin or a toxic effect of another gene.
Furthermore, the marker status at the MAPT locus correlated with more intense tau aggregates in the form of coiled bodies and tufted astrocytes, two of the standard diagnostic features of PSP. This reinforces the idea that tau overexpression is part of the pathogenesis of PSP and that inhibiting that expression could provide prevention.
So as the authors modestly conclude, “MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes.” All of these associations may suggest new drug targets, but it’s a long slog from there to the clinic. However, if someone screens a library of existing drugs for their ability to suppress overexpression of these proteins, the path to a treatment could be much, much shorter