Recommended Readings: Susan Lindquist, Ph.D. October 17

Friday Lecture Series
Friday, October 17, 2014
3:45 p.m., Caspary Auditorium

Susan Lindquist, Ph.D.
Professor of Biology,
Massachussetts Institute of Technology
Member,
Whitehead Institute for Biomedical Research
Investigator,
Howard Hughes Medical Institute

From Yeast to Patient Neurons and Back Again: Powerful Discovery Platforms Combatting Neurodegenerative Disease

Recommended Readings

Empirical Articles

Chung, C. Y., Khurana, V., Auluck, P. K., Tardiff, D. F., Mazzulli, J. R., Soldner, F., … Lindquist, S. (2013). Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science, 342(6161), 983–987. doi:10.1126/science.1245296

Tardiff, D. F., Jui, N. T., Khurana, V., Tambe, M. A, Thompson, M. L., Chung, C. Y., … Lindquist, S. (2013). Yeast reveal a “druggable” Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. Science, 342(6161), 979–983. doi:10.1126/science.1245321

Treusch, S., Hamamichi, S., Goodman, J. L., Matlack, K. E. S., Chung, C. Y., Baru, V., … Lindquist, S. (2011). Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer’s disease risk factors in yeast. Science, 334(6060), 1241–1245. doi:10.1126/science.1213210

Review Papers

Khurana, V., & Lindquist, S. (2010). Modelling neurodegeneration in Saccharomyces cerevisiae: why cook with baker’s yeast? Nature Reviews Neuroscience, 11(6), 436–449. doi:10.1038/nrn2809

Tardiff, D. F., Khurana, V., Chung, C. Y., & Lindquist, S. (2014). From yeast to patient neurons and back again: A powerful new discovery platform. Movement Disorders, 29(10), 1231–1240. doi:10.1002/mds.25989

Natural Dye Obtained from Lichens May Combat Alzheimer’s Disease

A red dye derived from lichens that has been used for centuries to color fabrics and food appears to reduce the abundance of small toxic protein aggregates in Alzheimer’s disease. The dye, a compound called orcein, and a related substance, called O4, bind preferentially to small amyloid aggregates that are considered to be toxic and cause neuronal dysfunction and memory impairment in Alzheimer’s disease. O4 binding to small aggregates promotes their conversion into large, mature plaques which researchers assume to be largely non-toxic for neuronal cells.  Read  the full story in NATURE CHEMICAL BIOLOGY.

A Fresh Look At The Validity Of Current Understanding Of Alzheimer’s Disease

For decades the amyloid hypothesis has dominated the research field in Alzheimer’s disease. The theory describes how an increase in secreted beta-amyloid peptides leads to the formation of plaques, toxic clusters of damaged proteins between cells, which eventually result in neurodegeneration. Scientists at Lund University, Sweden, have now presented a study that turns this premise on its head. The research group’s data offers an opposite hypothesis, suggesting that it is in fact the neurons’ inability to secrete beta-amyloid that is at the heart of pathogenesis in Alzheimer’s disease.  Read the report of their work in Journal of Neuroscience.

New Drug Target for Alzheimer’s, Stroke Discovered

A tiny piece of a critical receptor that fuels the brain and without which sentient beings cannot live has been discovered by University at Buffalo scientists as a promising new drug target for Alzheimer’s and other neurodegenerative diseases.

The research on the NMDA (N-methyl-D-aspartate) receptor was being published online  in Nature Communications.

Insulin Nasal Spray May Slow Alzheimer’s Disease

Intranasal insulin therapy may have beneficial effects on cognition and function among patients with Alzheimer’s disease, a pilot study suggested.

Patients who received 20 IU of intranasal insulin daily for four months had improvements on delayed story recall tests (P=0.02, Cohen f effect size=0.36), according to Suzanne Craft, PhD, of the Veterans Affairs Puget Sound Health Care System in Seattle, and colleagues.

And compared with placebo, baseline scores on the Dementia Severity Rating Scale were maintained over the study period in patients receiving either 20 IU or 40 IU of the insulin (P=0.01 for both, Cohen f = 0.38 for 20 IU and 0.41 for 40 IU), the researchers reported online in the Archives of Neurology.

More Genetic Basis for Alzheimer’s Risk

A pair of papers published in Nature Genetics reports on new genes associated with Alzheimer’s disease, bringing the total number of genes associated with the disease to 10, The New York Times says. One group of researchers studied Europeans with Alzheimer’s and the other studied Americans, and both groups homed in on similar genes. The newly unearthed genes increase a person’s risk of developing the disease by about 10 percent to 15 percent — a more modest effect than that of APOE, which can raises a person’s risk by 400 percent to 1,000 percent depending on the number of copies of the gene the person has.   Read the European study.     Read the American study.

Alzheimer’s Disease May Be Inherited From Your Mother

Results from a new study contribute to growing evidence that if one of your parents has Alzheimer’s disease, the chances of inheriting it from your mother are higher than from your father. The study is published in the March 1, 2011, print issue of Neurology.  The researchers found that people with a mother who had Alzheimer’s disease had twice as much gray matter shrinkage as the groups who had a father or no parent with Alzheimer’s disease. In addition, those who had a mother with Alzheimer’s disease had about one and a half times more whole brain shrinkage per year compared to those who had a father with the disease. Request article from Markus Library.

Genetic Basis of Brain Diseases

Scientists have isolated a set of proteins that accounts for over 130 brain diseases, including diseases such as Alzheimer’s disease, Parkinson’s disease, epilepsies and forms of autism and learning disability. The team showed that the protein machinery has changed relatively little during evolution, suggesting that the behaviors governed by and the diseases associated with these proteins have not changed significantly over many millions of years. The findings open several new paths toward tackling these diseases.   In the brain synapses have a set of proteins, which, like the components of an engine, bind together to build a molecular machine called the postsynaptic density — also known as the PSD. 

A team of scientists, led by Professor Seth Grant at the Wellcome Trust Sanger Institute and Edinburgh University, have extracted the PSDs from synapses of patients undergoing brain surgery and discovered 1461 proteins, each one encoded by a different gene. This has made it possible, for the first time, to systematically identify the diseases that affect human synapses and provides a new way to study the evolution of the brain and behaviour.    Read more in the Dec 19 issue of Nature Neuroscience.

The Hunt for Blood Biomarkers to Diagnose Alzheimer’s

Attempts to find a lone biomarker for Alzheimer’s disease — whether it’s in blood, spinal fluid, or the brain — have largely failed.  The Texas Alzheimer’s Research Consortium project conducted a longitudinal case-control study, using stored blood samples to develop an algorithm that separates patients with Alzheimer’s disease from controls. The biomarker assays looked at hundreds of proteins, including thrombopoietin, TNF-alpha, creatine kinase, and various interleukins.  The his team focused on a large array of blood-based proteins, since assay technology has now made it possible to evaluate large amounts of data.   Screening for these biomarkers and factoring in age, sex, education, and APOE status led to a sensitivity of 0.94 and a specificity of 0.84,  as reported by Sid O’Bryant, PhD, of Texas Tech University, in Lubbock, Texas, and colleagues in the Archives of Neurology.   They also saw that many of the proteins with the highest importance were inflammatory in nature, which suggests that the existence of an inflammatory-related endophenotype of Alzheimer’s disease “may provide targeted therapeutic opportunities for this subset of patients.”

Recommended Readings: Gizem Donmez, PhD Sept 27, 2010

Monday Lecture Series

The Role of SIRT1 in Neurodegenerative Diseases

Gizem Donmez, Ph.D.,

Post Doctoral Fellow 

Glenn Laboratory for the Science of Aging, Department of Biology

Massachusetts Institute of Technology

September 27, 2010

4:00 p.m.  Welch Hall Level Two

Recommended Review Article:

Haigis MC, Sinclair DA.  2010.   Mammalian Sirtuins: Biological Insights and Disease Relevance.
ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE   5: 253-295   

Recommended Readings:

Donmez G, Wang D, Cohen DE, et al.  2010. SIRT1 Suppresses beta-Amyloid Production by Activating the alpha-Secretase Gene ADAM10.    CELL    142 ( 2):320-332   

Albani D, Polito L, Forloni G. 2010.  Sirtuins as Novel Targets for Alzheimer’s Disease and Other Neurodegenerative Disorders: Experimental and Genetic Evidence.  JOURNAL OF ALZHEIMERS DISEASE 19(1): 11-26    PLEASE CONTACT MARKUS LIBRARY FOR A COPY OF THIS ARTICLE.

Gao J, Wang WY, Mao YW, et al.   2010.  A novel pathway regulates memory and plasticity via SIRT1 and miR-134NATURE    466( 7310): 1105-U120   

Michan S, Li Y, Chou MMH, et al.   2010.  SIRT1 Is Essential for Normal Cognitive Function and Synaptic Plasticity.   JOURNAL OF NEUROSCIENCE    30(29): 9695-9707   

Tang BL, Chua CEL.  2010.  Is systemic activation of Sirt1 beneficial for ageing-associated metabolic disorders?   BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS    391(1): 6-10

Tang BL.  2009.  Sirt1’s Complex Roles in Neuroprotection.   CELLULAR AND MOLECULAR NEUROBIOLOGY    29(8):1093-1103