Monday, August 24, 2009

Dr. Stephan

After a very challenging summer, I've finally turned in my written thesis, so it's official: I have my Ph.D. I'm publishing the abstract below. These findings should all be published in peer-reviewed journals in the next 6 months.


Ataxin-7 Conserved Motifs Determine the Severity of the Neurodegenerative Disorder Spinocerebellar Ataxia Type 7 in Transgenic Mice and Influence Lifespan in Yeast

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant, progressive neurodegenerative disorder whose characteristic features are cerebellar ataxia, dysarthria, and retinal cone-rod dystrophy culminating in blindness. SCA7 is caused by an abnormally long glutamine-coding CAG repeat in the SCA7 gene, which encodes the protein Ataxin-7.

Ataxin-7 contains several conserved motifs that may influence the toxicity of the glutamine tract. Among these are three conserved regions (conserved block I – III), two caspase-7 cleavage sites, a nuclear export signal and two monopartite nuclear localization signals (NLS). Previous investigations have shown that the caspase-7 cleavage site D266 is required for the full toxicity of the Ataxin-7 protein in cell culture. We generated SCA7 transgenic mice expressing a 92 CAG version of the human SCA7 cDNA, with and without a D266N mutation. Mice carrying the D266N mutation were protected from SCA7-like neurodegeneration, behavioral signs and shortened lifespan.

To further characterize the role of conserved motifs in SCA7 pathology, we generated SCA7 transgenic mice carrying point mutations in both C-terminal NLSs (KKRK -> KAAK). Previous work has shown that nuclear localization is an important step in the pathology of CAG repeat disorders. We observed that mice lacking C-terminal NLS activity were substantially protected from degeneration of the retina and cerebellum, SCA7-like behavioral signs and shortened lifespan.

Age is the primary risk factor for neurodegenerative disease. Even in the absence of overt disease, the aging brain shows histopathological and molecular changes reminiscent of neurodegeneration. To explore the link between neurodegenerative disease and aging, we have examined the replicative lifespan of Saccharomyces cerevisiae missing the SCA7 ortholog, SGF73. This strain exhibits an unusually long lifespan, which is dependent on the function of the NAD+-dependent deacetylase SIR2. We present evidence that the extended lifespan of the SGF73 null strain is due to the influence of Sgf73 on the activity of Sir2 and the histone deubiquitinase Ubp8. Furthermore, we show that the level of ubiquitinated H2B is elevated in an SCA7 transgenic mouse line, indicating that an alteration in Ubp8 activity may play a role in SCA7 pathology and that aging and neurodegeneration may share a common mechanism.

91 comments:

Peter Hoff said...

Congratulations,

Now you can spend 100% of your effort on this blog.

Thanks for the wonderful reading.

Dave in Ohio said...

Congratulations, Stephan.

Lisa said...

Congratulations, Dr. Stephan!! Wow, your blog output never revealed how much pressure you must have been under finishing the thesis. Well, except maybe when you suggested a certain persistent and contrarian commenter piss off, as I recall ... (and I'll confess to a lot of vicarious satisfaction on that occasion). Very best of luck with whatever comes next. My selfish hope is you'll be able to continue blogging here, but whatever you do, I think it's guaranteed you'll make significant contributions. Apart from all the brilliant analysis and creative thinking, you are just terrific at distilling and communicating complex information and ideas. Bravo!!!

Natural Athlete said...

Congrats man, that is title is quite a handful.

Don said...

Congratulations Stephan!

brentcu said...

Well done, Doctor. Go grab a beer at the Buckaroo in Fremont.

Kurt G. Harris MD said...

A hearty congratulations, Dr. Guyenet!

Inphidel said...

Congrats Dr. Stephan! A cheeseburger is in order...

john said...

way to go, man. sorry...dr. man.

Steve Parker, M.D. said...

And more congratulations, Dr. Stephan! A great accomplishment.

I suggest "a cure for Alzheimer dementia" as your next project. It's people like you who will find it. God bless you.

Dave said...

Congratulations! On to the "real world" . . . :-)

Phil said...

Congratulations, Stephan. So you were working on your dissertation in your spare time!

Dave Moss said...

Congratulations!
If your posts here suggest a fraction of the quality of your thesis then it'll be a valuable contribution indeed.

Jenny said...

Congratulations Dr. Stephan! How encouraging it is to know that someone of your intellectual caliber is in a position to do important genetic research.

Here's to your future Nobel prize!

Senta said...

Congratulations Dr. Stephan! We can all say, "we knew him when!" Please keep us posted on all your endeavors so we can cheer you on.

toddhargrove said...

Congratulations, Stephan.

Primitivo said...

Congratulations Dr. Stephan, a great scientific career is ahead of you now!

SeanBissell said...

Congrats! That's awesome! Great job!

Brock Cusick said...

And you've already updated your Blogger profile I see. :)

Congratulations Dr. Guyenet!

KKCorey said...

Congrats!

What's next?

Kennedy said...

Respect to you, from many top quality posts it's a fitting title!

Venkat said...

Woohoo!!. Congratulations Dr Stephan. I wish you a great carrier and time ahead.

Thanks

Venkat

Jeff said...

Congrats Dr. Stephan!

Maybe this post will be less controversial than the last. :-) I will look for email follow up just in case so I don't miss some fireworks.

jeff

Robert McLeod said...

Well hello Mr. Fancy-pants.

John said...

Lisa in comment #3 said it so well, I'll barefacedly steal most of her words:

Congratulations, Dr. Stephan!! Wow, your blog output never revealed how much pressure you must have been under finishing the thesis... Very best of luck with whatever comes next. My selfish hope is you'll be able to continue blogging here, but whatever you do, I think it's guaranteed you'll make significant contributions. Apart from all the brilliant analysis and creative thinking, you are just terrific at distilling and communicating complex information and ideas. Bravo!!!

Oh, and as Jenny said:

Here's to your future Nobel prize!

Pythonic Avocado said...

I'm very happy for you! Congratulations! And thank you again for all the work you put into your blog.

castlegrok said...

Congrats!!!

Love the site. Keep up the excellent work!

Chris said...

Congratulations!!

What next? Do you have an academic post to go to?

Aaron said...

Congrats! I'm 100% sure you've earned it.

Dr. B G said...

Congratulations Dr. Stephan!! Wonderful work! I don't know how you do it all...

Red Bridge... it's a sorghum, gluten-free beer! Ck it out!!

Lynn M. said...

Congratulations Stephen.

You didn't mention defending your dissertation, but if you have a PhD, I guess you're through that too.

P said...

WOW! Congratulations!!!

Jenny Light said...

Congratulations Stephan! I guess I need to hire a translator to understand just what your thesis was about, but it certainly sounds very important! I'm sure it will be of great help to all! Thanks again for all that you do!

Jeremy Fox said...

Awesome! What are your plans after graduation?

Helen said...

Congratulations, Stephan! I've wondered how you were able to do such a well researched and well written blog at the same time as getting a PhD - and still wonder. I hope you'll continue to be able to do the blog as you enter the "real world" of work. A selfish thought, perhaps.

Anyway, great work - sounds interesting!

Dexter said...

Stephan Guyenet, PhD. has a nice ring to it. Congratulations.

Now on to winning the Nobel Laurete
prize in neuroscience for discovering the cure for aging and neurodegeneration.

Please hurry...as I am 66 years old. If you happen to have any extended lifespan SGF73 you could send me, it would be most appreciated.

Leniza said...

Congratulations, Dr. Stephan!

Hans said...

Congratulation

Nancy LC said...

Congrats! You so deserve this!

Mee-Lise said...

Congratulations, Dr. Stephan! You certainly deserve it.

homertobias said...

Felicitations! Ok,Ok you. So what are you gonna do? I hope more of the same with more $$$$. You'd be a great teacher, that's obvious. Pass it on to the grad students with research and blogging on the side. In my realm, they'd call you a "PHUD". You would be a great "MUD-PHUD", but it is school forever. (MD/PHD) I personally think you should travel... and not to Las Vegas or Miami Beach.

Drs. Cynthia and David said...

Congratulations! I don't know about you, but writing my thesis was one of the hardest things I've ever done. Getting through that is no mean feat!

Good luck with your future directions. I'm excited to hear what you do next. I hope you can continue your excellent blog! And thanks for banning the annoying poster- I was turned off from reading comments by him/her.

Cynthia

arnoud said...

Awesome! Congrats Dr. Stephan.

Just one thing I have a hard time figuring out: all these top-notch posts, all the extensive research that goes into writing these, all the amazing follow up... a Ph.D. in neuroscience completed.... wonderful whole health cooking.... how do you get away with all that, and survive without sleep?

Carl M. said...

Congratulations! Now remember, when someone calls you Mr. Guyenet, extend your pinky towards your face and bluster:

"That's DOCTOR Guyenet!! I didn't spend 6 years in evil graduate school to be called Mister, thank you very much."

(Replace 6 with how many years you spent.)

Bryan - oz4caster said...

Congrats and good luck getting a decent job where you don't have to cater to preconceived conclusions on the work you perform :)

Hope you find time to keep up this excellent blog.

kat. said...

Congratulations, Stephan! Keep up the good work!

Dennis said...

Congratulations and best wishes!

I am very happy for you.

Eran said...

Congrats! This is one of my favorite blogs... keep up the good work!

Melchior Meijer said...

Congrats Stephan! Like many others, I'm sure you're heading for Stockholm.

Kevy said...

Congratulations Dr Stephen!!

Ditto Lisa - my life would not be quite the same without your posts to look forward to - I hope you find the time to continue.

I look forward to following your progress.

Best regards

Robert Andrew Brown said...

Very many congratulations Stephan

Aaron Blaisdell said...

Congrats and welcome to the club!

Diana Hsieh said...

Congratulations -- from one summer 2009 Ph.D to another!

(I can't believe that you were able to keep up your blogging so well. Clearly, you're way more awesome than me!)

Ben said...

Congrats

caseytoussaint said...

Congratulations - I've never commented here before, but I read your blog all the time. You do an amazing job of writing in an understandable way about very complicated subjects. Félicitations pour le doctorat!

Michael said...

Congratulations Stephan. A long hard climb up the mountain. Will you be staying in Seattle?

Michael

Anna said...

Congratulations, Dr. Stephan! I'm in awe of all you did on this blog while pursuing your education.

What are your post-doc plans?

medical center said...

information for cardiology
http://summary-of-cardiac.blogspot.com/
thank you dr stephan

MangoManDan said...

So, Ataxin-7 Conserved Motifs Determine the Severity of the Neurodegenerative Disorder Spinocerebellar Ataxia Type 7 in Transgenic Mice and Influence Lifespan in Yeast, eh?
Somehow I always suspected that would be the case ;<)
By the way, congratulations, and we wish you great success in all future endeavors.

Nick said...

A belated congratulations, Stephan! I remain deeply in awe of your mind.

Scott W said...

I'll add my congrats to everyone else's. Well deserved based on what I've seen here.

Scott W

Anne said...

One more congratulations, Stephan...um, I mean Dr. Stephen.

willismorse said...

Congratulations, Dr Stephan.

I'd like to point out that this is the first of your posts that is completely incomprehensible to me; I hope this isn't the start of a trend :-)

Seriously, your site is a wealth of information. Thank you for contributing so much to our knowledge.

Raul (hummingbird604) said...

Dr. Stephan :)

From one PhD (and blogger) to another one, congratulations! I know how hard it is to write a blog AND write a PhD thesis, trust me.

All the best,
Raul

Stephan Guyenet said...

Thanks for the congratulations and wishes, everyone.

Of course, no one actually has to call me Dr. anything. It's still just Stephan.

I'm planning to do a postdoc next, most likely in Seattle. There are a couple of very exciting labs that I'm considering at the moment.

I do plan to continue blogging. I should still have access to the amazing UW library system.

Ankur said...

A million congratulations to you !

Low-Joe said...

Congratulations, Dr. Stephan Guyenet and best wishes for the future!!!

Megan said...

Many congratulations, Dr Stephan!

gunther gatherer said...

well done stephen, and thanks so much for your informative blog.

Michael Gold said...

Congratulations!!

And thanks for the insightful, objective, rational analyses you provide here!

--Michael

Scott Miller said...

Huge congrats, Dr. Stephen.

I'm sure you will be an important influence within your profession, and part of a new generation pushing to turn the tide toward prevention versus profit.

angela said...

Congratulations, Dr. Stephan! from a silent reader and admirer of your blog.

Miki said...

Congratulations

It seems you have earned a second PHD from all of us here for Pushing the Hard Drive so eloquently in the service of humanity

Obama take notice!

Peter said...

Congratulations Dr. Stephan!
I, like many others, have never left a comment, but I have enjoyed all the info the blogs and discussions have provided me.
All the best to your future.
Thank you!

JohnN said...

Congratulations Dr. Stephan Guyenet! Is Guyenet of French origin?

Your accomplishments are nothing short of amazing: the submission of your thesis and a vast number of quality posts in the past year.

Best of luck to your bright future.
John

medical center said...

congratulations Dr.Stephan...
i hope i can become like you.
i'm medical student from indonesian.i interst in neurology science.
my first blog is about neurology and medical science..
i write more blog for more my saving. now i have new blog about cardiology...
if you have information about schoolarship, please send me email...thank you for your motivation....

fatlies said...

Congratulations Stephan!

Michael said...

Congratulations Dr. Guyenet!

Zbig said...

Congratulations, doctor! But please keep your great blog active whatever comes next!

Adam said...

Congrats Stephan! Thanks for writing this blog. I've learned a great deal from this blog and I definitely appreciate it.

L said...

congratulations. you should write a book. a new napd. may be end up on oprah. displace that douche dr oz.

Monica said...

A bit late seeing this as I've been away from a computer all week, but.... belated congratulations!!

Belmondo said...

Congratulations!

Steven said...

Congratulations! I've been enjoying your blog for a while now, and it has provided amazing insight as I work towards my masters in Sports Nutrition and Exercise science. Please, keep it up!

LeenaS said...

Congratulations, Stefan!
And all the best for your postdoc, too

Regards,
LeenaS

Senta said...

Wonder if he's still celebrating....


I miss Stephan!

Dr. Art Ayers said...

Congrats! You must have blogged to keep your sanity. I didn't blog then and you can see the result.

My advice to you is to postdoc forever. Believe me, the responsibilities of professorships weigh more heavily than the increased prestige/pay. Enjoy your freedom, live in other parts of the world and publish with abandon.

Enjoy your accomplishments now.

What is your next intellectual frontier?

Stephan Guyenet said...

Thanks Art. I'll be doing a postdoc in the lab of Dr. Michael Schwartz in Seattle. He studies bodyweight regulation and diet-induced metabolic dysfunction in rats. He's done some really interesting studies. I'm currently grappling with the fact that the most commonly used model of diet-induced obesity/metabolic dysfunction in rats is high-fat feeding. I'm trying to get him interested in the role of PUFA in health.

chasmyn said...

Congratulations!

I cannot help but notice your work is specific to SCA7.

My mother has SCA6.

I am wondering if you did any studying effects of diet or if you think diet would have an effect?

Stephan Guyenet said...

Hi Chasmyn,

I wish I knew something about the effect of diet/lifestyle on SCA6 or any of the other SCAs. No research has been done on it to my knowledge.

chasmyn said...

That was my suspicion. The only thing I've seen related to diet with SCA is celiac - gluten sensitivity.

I suspect not just gluten but all grains, but that's me. I find that I do best personally with no grains whatsoever in my diet, and as she is my mother, I suspect the same for her.

It all goes back to the gut.

I tried to share that information with my mother - sent her the research papers, etc. I'm not sure she is really open to my suggestions anyway, but if there was real research, maybe she would listen.

Anyway, enough about me. Thanks so much for your response.