Expert update on PSP/CBD genetics study

Thursday’s CurePSP webinar with Dr. Yvette Bordelon included an update by Dr. Schellenberg of UPenn on the PSP and CBD Genetics Program. It was great to get this update from the expert. I thought it warranted its own (shorter) webinar.

What follows are my notes on Dr. Schellenberg’s presentation, a short comment made by Dr. Bordelon on the study’s findings, and some of my own comments.

Further down is the email I sent out to the local support group on 10/1 with a short update on the genetics study and some general background about the study. Just as Paul Freeman (CurePSP board member) told us in September at a local support group meeting, four new genetic mutations associated with PSP have been discovered through this brain research.


Presenter – Gerard Schellenberg, PhD
Univ of Pennsylvania School of Medicine

Topic – Charles D. Peebler Jr. PSP and CBD Genetics Program

What does it take to get PSP or CBD (at least in terms of the genetic components)?
* The bad form of one gene is very rarely the cause of PSP or CBD. What this means is that if you have a family member with PSP or CBD, your chances of developing the disease is pretty remote. In contrast: there are diseases, such as Huntington’s Disease and some forms of ALS, where a single gene is involved, and if you inherit the bad form of that gene you will get the disease. This type of genetics — “single gene inheritance” — tracks very strongly in families.
* Most cases are caused by the bad form of 5 to 10 genes. For each bad copy inherited, risk is increased. If you develop the good form of each of these genes, your chance of developing PSP or CBD is very low.
* We think there also might be some environmental insult involved. We don’t really have a good handle on what the environmental input is.

Goal: identify ALL the genes that contribute to PSP/CBD. They aren’t focusing on one gene, as this is rare. Put another way: they are focused NOT on the genes that cause PSP and CBD but rather on the genes that contribute to the risk of PSP and CBD.

This genetics study requires:
* DNA from a large number of autopsy-confirmed cases of PSP and CBD
* DNA from a large number of cases of those who do not have PSP or CBD. This is compared to the DNA from those who do have PSP or CBD.
* Genetic technology to study all regions of all chromosomes (across the genome or genetic material)
* A statistical analysis team

This is an international effort:
Germany (Dr. Muller, Dr. Hoglinger)
US: Mayo Jax (Dr. Dennis Dickson)
UK: Queen’s Square (Dr. Andrew Lees – one of the international experts on PSP and CBD, Dr. Rohan Silva)

Brains collected by the German team:
Munich – 8 CBD, 21 PSP
Wurzburg – 2 PSP
Barcelona – 3 CBD, 17 PSP
Netherlands Brain Bank – 23 PSP
London Brain Bank – 2 CBD, 8 PSP
Saskatchewan, Canada – 37 PSP
Wilrijk, Belgium – 2 PSP
Australian Brain Bank – 1 CBD, 9 PSP
Pamplona, Spain – 1 PSP
Subtotal – 14 CBD, 125 PSP

Other brains contributed:
Mayo Clinic Brain Bank – 78 CBD, 599 PSP

Other brains contributed:
Queen’s Square Brain Bank (London) – 144 PSP

Brains collected by Dr. Schellenberg from US-based institutions:
Emory Univ – 13 CBD, 6 PSP
McLean Brain Bank – 8 CBD, 64 PSP
Indiana – 12 CBD, 31 PSP
Los Angeles VA/UCLA – 1 CBD, 14 PSP
Massachusetts General – 34 PSP
NY Brain Bank – 6 CBD, 22 PSP
Rancho Los Amigos Medical Center – 3 PSP
Sun Health Research Institute – 38 PSP
Univ of Michigan – 23 PSP
UPenn CDNR – 30 CBD, 51 PSP
Univ of Washington – 4 PSP
Univ of Southern California – 2 PSP
Univ of Texas Southwestern – 6 CBD, 14 PSP
Johns Hopkins – 27 PSP
Subtotal – 75 CBD, 343 PSP

Total brains (or samples) contributed over the last two years:
CBD: 168
PSP: 1212
total autopsy-documented cases: 1380

In addition to the 1380 PSP/CBD samples, they have DNA from 3000 controls. These controls are healthy children who have come into the Children’s Hospital of Philadelphia for routine check-ups.

The genetic technology being used tests 660,000 sites across the human genome (all the inherited material or all of the inherited DNA). We can pretty much test everywhere in the human genome for change related to PSP and CBD.

What we learned through this study, after the statistical analysis: we learned about four new genes that are involved in one’s risk of developing PSP or CBD. We didn’t previously know about genes on chromosomes on 1, 3, 11 and 12. We knew about the tau genetic mutation on chromosome 17. This knowledge about four new genes is the exciting pay-off from two years of very hard work. Each of these genes tells us something about the mechanism or the pathway for how PSP or CBD develops.

* explore how each of these genes plugs into the disease. This knowledge is critical to understanding what causes it and what causes it to progress to the point where symptoms start to appear.
* explore how genetics and the environment interact

A lot of pharmaceutical discovery is based in part on genes found through these methods. This has been particularly true in Alzheimer’s Disease. Genetics findings are really driving a lot of the pharmaceutical discovery efforts by the big companies.

Next specific steps in this study:
* analyze tau in more detail. How does the bad form of tau contribute to risk? Is it simply making more tau protein or something more complicated?
* replication studies to verify these are not statistical artifacts. We are collecting 1000 more PSP cases to look at these four genes and tau. [Robin’s question: are they collecting more CBD brains as well?] * identify additional genes with the additional samples

* The genetic experiment worked! And it worked spectacularly!
* 4 new genes previously not implicated in PSP or CBD
* potential for identifying new genes (which gives us insight into the disease process)
* potential for new leads for therapeutics to treat or prevent PSP or CBD

Thank you:
* families that contributed DNA. These contributions are absolutely essential.
* CurePSP that took a risk and put up a large amount of money for this study
* donors to CurePSP to make this research possible, particularly the Charles Peebler Jr. family

Comment by Dr. Yvette Bordelon on Dr. Schellenberg’s presentation:

This is spectacular! These are very exciting results for PSP and CBD.

These genome-wide screens have been attempted in other disorders, and haven’t been nearly as successful. In PD several attempts have been made, none of which have shown clear correlations.

Robin’s notes:

In a recent letter to a brain donor’s family, Mayo Jax confirmed the PSP diagnosis and indicated that it had 730 PSP brains in its brain bank. Dr. Schellenberg reported above that 599 PSP brains were included in the original group. Presumably the additional 131 brains collected thus far at Mayo Jax will be part of the goal of collecting 1000 more brains.

If your loved one has donated tissue to an institution not listed above (such as UCSF or the Univ of NM, to name two that I know have PSP or CBD brains), please contact the neuropathologist to find out if samples can be provided to Dr. Schellenberg to reach the goal of 1000 more brains.

I’m proud to report that I’ve played a role in having 15 path-confirmed PSP or CBD brains donated to institutions listed above as study participants. Most of these donations have been to Mayo Jax. (I’ve played a role in many more brains being donated to Mayo Jax for other disorders, and to other institutions not yet participating in the PSP/CBD study.

Date: Thu, 01 Oct 2009 20:58:13 -0700
To: local PSP/CBD support group
From: Robin
Subject: Small update on PSP/CBD genetics study

As many of you know, CurePSP (the new name for the Society for PSP) began the multi-year Genetics Consortium a couple of years ago. This description is from the 2008 CurePSP annual report:

“The CurePSP Genetics Program is a multi-year venture sponsored and supported by CurePSP (The Society for Progressive Supranuclear Palsy). Our goal is to search the entire genome for genes related to PSP and CBD and to identify previously unsuspected abnormal biochemical pathways against which scientists may be able to target therapeutic interventions. All activities will be carried out by the CurePSP Genetics Consortium, composed of neurologists, geneticists, and other scientists from the United States, the United Kingdom, and Germany working in collaboration with neuroscientists throughout the world.”

You can find a good layperson-oriented description of the genetics program starting on page 51 of the CurePSP 2008 annual report available online here: … 202008.pdf

Last year, about this time, it was reported that the goal was to have 1000 PSP brains included in the study but they ended up with 1300 PSP brains. I’m unclear as to how many CBD brains were examined but I’m assuming it’s several hundred.

Certainly all of the PSP and CBD brains donated to Mayo Jax were included in the study, as the brain bank there has several hundred PSP brains and around 100 CBD brains, and Mayo Jax is part of the research consortium (though it’s not the lead institution). …

If your loved one has donated brain tissue to a brain bank other than Mayo Jax, perhaps you can inquire if the tissue was sent to the Genetics Consortium for study. …

This is a genome study or a DNA study. The goal is to find out what genes or genetic mutations are implicated in PSP and CBD. Some gene chip technology that became available in 2007 (out of the Human Genome Project) has made the study possible, along with the brain donations and some serious funding.

Recently, Ed Plowman described the study in this way: “Each brain tissue sample had a computer chip assigned to it. The project is attempting to analyze what all PSP brains might have in common genetically that is different from non-PSP brains. As I understand it, hundreds of thousands of bits of data from each tissue sample are cataloged and the findings compared with all the other samples. It may be quite some time before the analysis is complete and findings released.”

So….now we are *finally* to the “small update” part of this email. Paul Freeman, the CurePSP Board’s Treasurer attended our most recent support group meeting, and sat with the PSP/CBD group. He indicated that four genetic mutations have been discovered as being culprits in PSP. (He didn’t say if these genes were also implicated in CBD.) He said that the researchers are going through the data again to confirm these findings, and then a paper will be written. This gets us a step closer to being able to do genetics testing and to find therapeutic interventions. It does seem like important progress along the way.