Express yourself, or better yet, don’t.

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

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Road test for a Roadmap

This is a request for your suggestions to improve/amend CurePSP’s research plan, which is now two years old.

Here’s a link to the first and current version of our Research Roadmap:  Roadmap for Symposium 2013. You can also find it here.

It was designed as a guide to grant applicants and donors who want to know what CurePSP is interested in funding.  That’s not to say that we wouldn’t fund other things, but proposals that fit into the Roadmap’s model are viewed more favorably in our grant review process.

The elevator explanation of the model is that it uses unbiased gene searches to identify new risk genes, then finds drug targets among the proteins in the related gene products or cellular pathways, then tests those drugs in lab models, then turns to Pharma to develop those drugs clinically.  Along the way, it calls for new models and new clinical markers to assist in the process.

Clearly, The Roadmap ignores important things such as symptomatic treatments, toxic etiologies, clinical characterization, epidemiology and neurophysiologic analysis, not to mention serendipitous neuroprotective treatments with unclear mechanism.  But it provides a focus and an orientation.

So please use the Comments function to leave me your suggestions for improvement.  Keep in mind that the Roadmap should remain relatively simple and generic.  We don’t want to direct research from the top down.  On the other hand, we don’t want the document to be so generic as to be useless.

Obviously, feel free to respond to others’ comments; and have fun!

 

A new PSP genetic risk factor screener

Genetic screening is emerging as a routine and necessary step in clinical research in the neurodegenerative diseases. If you’re looking for the cause of a family cluster, for example, you have to rule out the genetic variants already known to be associated with that disease. If you’re working up a geographical cluster of PSP, as my colleagues in France and I are, you have to look for a genetic founder effect before embarking on a difficult search for environmental causes, and the place to start is with gene variants already known to increase disease risk.
Pathological overlap among the various neurodegenerative diseases is another major current theme. For example, LRRK2 mutations can cause any of a number of pathologies, including PSP, and the tau H1 haplotype is associated with PSP, CBD and PD. It would therefore be convenient to have a single genetic screening device would allow different labs studying different diseases to compare or merge results.
Such a gizmo is now here. It’s a superset of Illumina’s Infinium HumanExome BeadChip called NeuroX. It tests for not only the standard 242,901 gene variants usable in studying any condition but also an additional 24,706 variants focusing on Alzheimer’s, Parkinson’s, MSA, ALS, FTD, multiple sclerosis, Charcot-Marie-Tooth disease, myasthenia gravis — and PSP. The chip is designed to allow easy substitution of subsequent versions of both the basic Illumina chip and easy addition of new neurological variants.
The first author of the report in Neurobiology of Aging is Mike Nalls and the senior author is Andrew Singleton, both of the NIH. The genetic variants included in the chip were derived from multiple genome-wide analyses over the past 20 years. Disclosure: I’m listed way down on the list of “authors” because I was a leader of “GenePD,” one of the consortia whose findings were used in constructing the new chip.  But I have no financial interest in the invention.
At a cost of $57 per sample plus the cost of the basic machine and technician time, you won’t have to be a drug company or the NIH to afford a statistically meaningful series; genetics core labs will be able to offer this as a routine procedure.

Is DNA methylation the key?

Very cool paper in PLoS Genetics this week reporting alterations in DNA methylation in PSP.  It’s from Giovanni Coppola’s lab at UCLA, with Yun Li as first author and collaborators from UCSF.  They used Illumina probes to profile DNA methylation genome-wide in WBCs.  The result was that in PSP, MAPT showed more methylation than controls or subjects with FTD.  But the same was true for three other genes near MAPT: KIAA1267, ARHGAP27 and DND1.  All lie within the H1 haplotype block, an inversion spanning 1.8 Mb and 48 genes at 17q21.31.

A new statistical technique called “causal inference” suggested that something in the H1 haplotype caused the differential methylation, which in turn caused the PSP phenotype.  They conclude that a quantitative trait locus for methylation exists within the H1 haplotype, but that differential methylation is a characteristic of H1 independent of the presence of PSP.

A supplemental experiment looking for differences in gene expression correlating with methylation changes came up empty, unfortunately.

So now we have evidence that the pathogenetic mechanism of the H1 haplotype is differential methylation of MAPT and/or nearby genes.  Work by others has suggested that H1 operates, rather, by increasing MAPT expression, but that observation is not consistently replicated.  Either way, we still have to explain what else is necessary to the etiology of PSP.  After all, H1 is present in 95% of subjects with PSP aut also in a majority of the rest of the population.

Do any geneticists out there have any special insights to share?