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

Is PSP the route to not just Alzheimer’s but also Parkinson’s?

We’ve known for many years that Parkinson’s disease, which the textbooks call an α-synucleinopathy, has some aggregated tau as well. It appears that each of the two proteins, once misfolded, not only induces its own normal brethren to misfold, it also induces copies of the other to misfold.
The first demonstration of this synergistic misfolding and resulting aggregation came in a series of three papers between 2002 and 2004 from the lab of John Trojanowski and Virginia Lee at Penn. The first authors were John Duda, Bernard Giasson and Paul Kotzbauer. (Disclaimer: I was one of their co-authors on all three.)

Now, Julia Gerson, a grad student in the lab of Rakez Kayed at the University of Texas Galveston, has presented work at the Society for Neuroscience that harnesses that finding of a PD/tauopathy overlap for therapeutic purposes. (Another disclaimer: Kayed has a related grant from CurePSP, where I chair the grant review.)

Gerson and friends created antibodies directed at oligomeric tau, which is tau in small aggregates of maybe 20 or 30 molecules, which are still small enough to remain in solution in the cytoplasm and therefore invisible to light microscopy, unlike mature neurofibrillary tangles. They didn’t want to target normal, non-aggregated tau for fear of disrupting the normal function of that protein, which is to stabilize microtubules.

They injected those anti-tau antibodies into mice that had a copy of a variant of the human gene encoding α-synuclein. The variation was an G209A mutation, producing an A53T alteration in the resulting protein. This is the mutation that my colleagues and I found in 1997 as the cause of PD in a large Italian-American family with autosomal-dominant PD, a finding that first linked PD with α-synuclein. (That’s Disclaimer #3. You’re starting to see why I’m so interested in this new finding.)

The antibody protected the mice against the loss of dopaminergic neurons that the α-synuclein mutation caused in the untreated mutant mice. Mice that received antibody against normal tau did even more poorly than the controls.

So here’s the take-home: Developing an anti-tau antibody for treatment of PSP may also help Parkinson’s. We already expect that it may help Alzheimer’s because that’s clearly a tau disorder. But now, the synergistic toxicity of tau and α-synuclein could also allow a single anti-tau antibody to protect against both Parkinson’s and dementia with Lewy bodies (which also has aggregation of both proteins).

If I were the drug companies, I’d be sitting up and taking notice. Two companies, Bristol-Myers Squibb and AbbVie (licensing an antibody from C2N) have already started anti-tau antibody trials in people with PSP. Others have anti-tau programs in progress.

This new report, which may extend the utility of those products to Parkinson’s, should give that snowball an extra push.

Just a residue full of sugar . . .

I’ve been jolted out of my non-posting torpor by CurePSP’s annual International Research Symposium, held on November 6 in La Jolla. The lecture hall was smack dab on the beach and despite the quality of the presentations, it was easy for the eye to wander from the lectern to the doorway framing a view of swaying palms and the blue Pacific. Thanks to Jeff Friedman for arranging the venue. Anyway, I’ll be describing some of the goings-on in this post and the next few.
Two of the presentations, both from pharma scientists, described drugs in development for PSP that reduce tau aggregation by inhibiting OGA (O-GlcNAcase; pronounced “oh-GLY-na-kaze”). That enzyme removes the sugar N-acetyl-beta-D-glucosamine from either serine or threonine residues of proteins. The opposing reaction, catalyzed by O-GlcNAc transferase, like other post-translational modifications, is a common way for cells to regulate proteins. In the case of tau, having that sugar in place reduces aggregation.
All of the OGA inhibitors being developed are small molecules suitable for oral administration. The smaller company with an OGA inhibitor program is Asceneuron, based in Lausanne, Switzerland. They expect to start a Phase I human trial in 2016 although they are still in an early stage of mouse model trials and they haven’t settled on one lead compound for further development. The larger company, Merck, is at a more advanced stage. Their drug, MK-8719, has shown that it can slow brain degeneration in mice transgenic for one of the FTD MAPT mutations. The drug also inhibits tau aggregation in a human iPSC line and in an early Phase I human trial in healthy volunteers was found to be well-tolerated and to increase O-GlcNAcylation in blood mononuclear cells.
Let’s hope that both companies move their OGA inhibitors to Phase II trials in the next couple of years.

A welcome formality

I see my patients with PSP on special clinic days when I have arranged for specialized professional help and have allotted extra time for the visits. The downside is that that it can be a dispiriting few hours, with little to offer anyone that day beyond symptomatic treatment, information and a pep talk. So I use this blog to accentuate the positive.

In that vein, I’m happy to report the drug/biotech industry’s efforts to develop a therapeutic antibody are proceeding apace. The latest tidbit is that the FDA has granted orphan drug status to the anti-tau antibody designated C2N-8E12 being developed by a joint venture of C2N Diagnostics and Abbvie. A 32-patient Phase I trial headed by Adam Boxer at UCSF will begin sometime soon. Achieving orphan status allows the company certain financial advantages and a longer patent life. Both are critically important for any new treatment for a rare disease, as the potential profits wouldn’t otherwise justify the development cost and risk.
Several other companies are working on anti-tau therapeutic antibodies, many of them aiming initially at PSP. Their ultimate Holy Grail is a treatment for Alzheimer’s, but it’s easier to conduct a clinical trial in PSP, as its progression is more readily predicted and measured. Furthermore, tau is the only protein known to aggregate in PSP, which makes that disease a simpler “model system” than AD, where both tau and beta-amyloid aggregate. The company furthest along this road is Bristol-Myers Squibb, whose tau antibody trial seeks 48 patients with PSP at 12 centers across the US and will start enrolling in a few weeks.
So I’m hoping for sunnier PSP clinic days soon!

A new drug target from an epidemiologic observation

I think what jolted me out of my multi-month posting torpor is next week’s annual meeting of the Movement Disorders Society. I’ve been preparing a lecture on the treatment of PSP, CBD and MSA, and that got my juices flowing.
Speaking of treatment, an interesting paper that appeared in Plos One during my writer’s block came out of Günter Höglinger’s lab in Munich. Julius Bruch was first author. It builds on the observation that people with Guadeloupean tauopathy are far more likely than local controls to have consumed the fruits sweetsop and soursop, which contain annonacin, a mitochondrial Complex I inhibitor. Subsequent work with annonacin has suggested that it can cause a tauopathy in rats.
The new paper found that annonacin upregulates the production of 4R tau, the predominant form in PSP and some other tauopathies, by favoring the inclusion of the exon 10 peptide product into the finished tau molecule. Further experiments described in the same paper showed that annonacin upregulates the splicing factor SRSF2, which is one of a handful of factors known to regulate splicing of exon 10. So they used silencing RNA to knock down SRSF2. The result was a dramatic reduction in 4R tau.

They then took the next step and analyzed human PSP brain tissue for SRSF2, finding it markedly elevated compared to controls with no neurological disease.

To examine the possibility that the elevation of 4R tau and SRSF2 by annonacin was the result of mitochondrial Complex I inhibition rather than of nonspecific cellular stress or nutrient deprivation, they treated neuronal cultures with MPP+, a well-studied Complex I inhibitor, but not with 6-hydroxydopamine, a toxin that works independent of Complex I, or with nonspecific nutritional deprivation.

So it looks like a drug that inhibits SRSF2 could correct the abnormal 4R/3R ratio in PSP and potentially prevent cell loss. But a lot of work remains to determine how important this particular pathway is in causing the cell loss. The highly variable 4R/3R concentration across different brain areas in PSP and the existence of tauopathies with normal or low 4R/3R ratios show that the story isn’t so simple. But with the recent explosion of interest from drug companies in PSP as a route to Alzheimer’s disease, any new approach could attract interest, and this one deserves a place on the list.  I don’t know if any existing or approved drugs inhibit SRSF2, but that could be a good job for a lab that’s tooled up for high-throughput screening.

PSP markers in CSF? Not yet

As a PSP-ologist, it takes a lot to discourage me, but the excellent review of CSF markers in the diagnosis of PSP did it. Nadia Magdalinou, Andrew Lees and Henrik Zetterberg of University College London, writing in the JNNP, point out that no CSF measure has been consistently or reproducibly found to differentiate PSP from all of the relevant competing diagnostic considerations.
An excellent study cited in the review found low levels of CSF α-synuclein in Parkinson’s, DLB and MSA relative to PSP and other brain disorders. A value less than 1.6 pg/μl had good (91%) positive predictive value for any synucleinopathy but higher concentrations had poor (20%) negative predictive value.  So that measure is of some small value.
Neurofilament light chain in CSF is elevated in PSP, MSA and CBD, according to another study, with an area under the ROC curve of 0.93. This has been confirmed by others since. This is useful in distinguishing PSP from PD, but when your patient has a poor levodopa response and downgaze problems, PD isn’t really the issue; PSP, MSA and CBD are.
One study of neurofilament heavy chain found that it can differentiate PSP from CBD but not from MSA. That study was published in 2006 and we’re still awaiting confirmation.
You’d think that tau would be the object of intense scrutiny in the differential diagnosis of PSP by CSF, but there’s been relatively little on that. One good study found that the ratio of phospho-tau to total tau is lower in PSP and MSA than in PD. The other studies of phospho-tau in PSP have been negative.
So the winner so far for PSP, limping across the finish line, seems to be neurofilament light chain. It’s not available commercially as far as I can tell; nor should it be, without further study.
Adding to this discouraging picture is the fact that most or all of the studies of CSF markers in PSP have sampled patients in a stage of PSP that allowed clinical diagnosis. By that time, the CSF picture may be more diagnostic than in the earlier stages, when a state marker would be most useful. In other words, the studies were retrospective rather than prospective.
For now, I’m putting my money on imaging.