What a failed drug does (and is there hope for latrepirdine?)

Latrepirdine (Dimebon) was initially used as an antihistamine drug in Russia. It was later found to be neuroprotective, and entered phase II clinical trials in the US for both Alzheimer’s disease and Huntington’s disease. However, Dimebon failed in a US-based phase II replication trial of a prior successful Russian phase II trial of mild-to-moderate AD. Given the initial promise of the drug and split results,  as well as the lack of treatments for neurodegenerative diseases, there in is significant interest in understanding the underlying molecular mechanism(s) for the drug’s effects.

In a paper appearing this week in Molecular Psychiatry, Brandeis researchers in the Petsko-Ringe lab, including postdoc Shulin Ju and undergraduate Jessica Liken ’11, used yeast models of neurodegenerative disease associated proteins to show that Dimebon specifically protects yeast from the cytotoxiciy of α-synuclein, a protein involved in Parkinson’s disease. They further showed that protection is mediated through its up-regulation of autophagy pathway. In collaboration with Sam Gandy‘s group at Mount Sinai School of Medicine, these findings were further confirmed and validated in neuronal cell and animal models.

Given these observations, disparities in the contribution of α-synuclein to the neuropathology between the Russian and US Dimebon studies might also explain, at least in part, the inconsistency of the cognitive benefit in the two trials. If this speculation is correct, then it may be interesting to test for benefits of Dimebon in treating synucleinopathies such as Parkinson’s disease, Lewy body dementia, REM sleep disorder and/or multiple system atrophy.

see also: press release from Mt. Sinai Alzheimer’s Diesease Research Center

Steele JW (*), Ju S(*), Lachenmayer ML(*), Liken J, Stock A, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Protter AA, Martins RN, Ehrlich ME, Yue Z, Petsko GA, Gandy S. Latrepirdine stimulates autophagy and reduces accumulation of alpha-synuclein in cells and in mouse brain. Molecular psychiatry. 2012.

Steele JW(*), Lachenmayer ML(*), Ju S, Stock A, Liken J, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Fraser P, Westaway D, St George-Hyslop PH, Szabo P, Relkin NR, Buxbaum JD, Glabe CG, Protter AA, Martins RN, Ehrlich ME, Petsko GA, Yue Z, Gandy S. Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer’s mouse model. Molecular psychiatry. 2012.

Biochemistry Senior Research Talks on April 29

The Department of Biochemistry presents senior research talks by the 2010/2011 Biochemistry Honor and BS/MS Candidates on Friday, April 29, 11:30-1:30pm in Gerstenzang 121.

Benjamin D. Hornstein – BS/MS
Seq A: construction and analysis of mutants
Advisor: Sue Lovett

Marcus R. Kelly- BS/MS
Replacement Matrices for Transmembrane Proteins
Advisor: Douglas Theobald

Yuliya Y. Mints – BS/MS
Inosine Monophosphate Dehydrogenase and Transcription: a mechanism for retinitis pigmentosa?
Advisor: Liz Hedstrom

Sarah Naomi Olsen – BS/MS
Isolation, Purification, and Characterization of (+)-4R-limonene synthase
Advisor: Dan Oprian

Benjamin M. Whitlock – BS/MS
PABPN1 and SKIIP: A putative mechanism for the onset of Oculopharyngeal Muscular Dystrophy
Advisor: Dagmar Ringe

Philip D. Lessans – BS
Developing a Method of Extracting Native U snRNPs from eukaryotic cells using Snurportin 1 constructs
Advisor: Daniel Pomeranz Krummel

Jessica P. Liken – BS
Deletion Library Screen for Enhancers and Suppressors of ALS-associated FUS/TLS Toxicity in Yeast
Advisor: Greg Petsko

Everyone is welcome and encouraged to come. Pizza will be provided.

Two more NSF GRFP fellowship winners

Brandeis had 1 current undergraduate, 7 undergraduate alunmi, and 1 incoming graduate student win NSF graduate research fellowships this year. In addition to those cited below, Richard Stefan Isaac ’10 and Orly Wapinski ’09 were also selected. Isaac graduated magna cum laude with a BS/MS degree with high honors in Biochemistry. His thesis work “Functional Characterization of Regulators of Bacterial Pathogenicity and
” was done in the Petsko/Ringe lab. His work teaching in the Biology laboratory also resulted in a paper  in CBE Life Science Education. Isaac is currently a graduate student at Univ. of California, San Francisco. Wapinsky received a BS degree with Highest Honors in Biology, doing in her thesis work “Characterization of Interferon Regulatory Factor-4 mutants” with Professor Ruibao Ren. Wapinski is currently studying at Stanford.

13th Annual Northeast Student Chemistry Research Conference (NSCRC)

The timing and location of this conference would seem to make it ideal for undergraduates to present their research — follow the links below if interested.

April Jewell of the NSYCC wrote:

As Chair of the Northeast Section Younger Chemist Committee (NSYCC), I would like to invite the Undergraduate and Graduate Students and Post-Doctoral Candidates from your department to participate in the 13th Annual Northeast Student Chemistry Research Conference (NSCRC). I would appreciate it if you would forward this information on my behalf. The NSCRC will be held at Northeastern University’s Curry Student Center on Saturday, April 30th, 2011.

The Northeast Student Chemistry Research Conference (NSCRC) is organized for students by students. It is devoted to the research of undergraduate, graduate, and post-doctoral chemistry students, providing a relaxed atmosphere for students to share their work. The day-long event features student poster and oral research presentations, a keynote speaker, awards, and catered lunch. The conference encourages students to network and get feedback from their peers. The 1st NSCRC was held April 24, 1999 at the Massachusetts Institute of Technology (MIT).

The deadline for abstract submission is Friday, April 8th, at 5pm. Please visit our website at nsycc.org for submission instructions.

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