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Acetylation may contribute to dementia and Alzheimer's disease; May lead to new treatments

Date:
September 23, 2010
Source:
Cell Press
Summary:
A new study uncovers a protein modification that may contribute to the formation of neuron-damaging neurofibrillary tangles in the human brain. The research may lead to new strategies for treatment of neurodegenerative diseases that result from pathological aggregation of tau protein.

A new study uncovers a protein modification that may contribute to the formation of neuron-damaging neurofibrillary tangles in the human brain. The research, published by Cell Press in the Sept. 23 issue of the journal Neuron, may lead to new strategies for treatment of neurodegenerative diseases that result from pathological aggregation of tau protein.

Tau protein is common in the central nervous system where it helps to stabilize microtubules that form the neuronal cytoskeleton. Tau mutations have been linked with dementia and Alzheimer's disease (AD), and accumulation of phosphorylated tau protein (p-tau) has been implicated in neurodegeneration. However, the molecular mechanisms that underlie abnormal tau aggregation have not been elucidated.

"We know that an enzyme called SIRT1 is reduced in the AD brain and that this reduction correlates with the accumulation of p-tau. Further, overexpression of SIRT1 protects against neuronal loss in a mouse model of AD," explains senior study author, Dr. Li Gan from the Gladstone Institute of Neurological Disease in San Francisco, California. "However, how SIRT1 protects against tau-mediated neurodegeneration is not clear."

SIRT1 is a deacetylase, an enzyme that removes acetyl groups from proteins. Like phosphorylation, acetylation regulates many different cellular functions, including cytoskeleton dynamics. "To determine whether tau is acetylated and whether tau acetylation contributes to tau accumulation, we investigated tau acetylation in neurons, mouse models of tauopathy, and AD brains," says Dr. Gan.

Dr. Gan's group found that tau acetylation prevents degradation of p-tau, and patients at early and moderate stages of tauopathy exhibited elevated tau acetylation. The researchers went on to show that inhibiting SIRT1 increased levels of acetylated and pathogenic tau while a small molecule inhibitor of p300, an enzyme known to attach acetyl groups to proteins, promoted tau deacetylation and eliminated p-tau associated with pathological conditions.

While the link between tau acetylation and tau phosphorylation is not known, the results provide new insight into tau-mediated neuropathology. "Our findings support the model that the abnormally elevated acetylation at an early stage of the disease could block clearance of p-tau from neurons, leading to its accumulation," concludes Dr. Gan. "Our observation that p300 diminished tau acetylation and effectively eliminated p-tau supports the idea that interfering with tau acetylation may be a new approach for reducing tau-related pathology."

The researchers include Sang-Won Min, Gladstone Institute, University of California, San Francisco, CA, University of California, San Francisco, CA; Seo-Hyun Cho, Gladstone Institute, University of California, San Francisco, CA, University of California, San Francisco, CA; Yungui Zhou, Gladstone Institute, University of California, San Francisco, CA; Sebastian Schroeder, Gladstone Institute, University of California, San Francisco, CA, University of California, San Francisco, CA; Vahram Haroutunian, The Mount Sinai School of Medicine, New York, NY; William W. Seeley, University of California, San Francisco, CA; Eric J. Huang, University of California, San Francisco, CA; Yong Shen, Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ; Eliezer Masliah, University of California at San Diego, La Jolla, CA; Chandrani Mukherjee, Johns Hopkins University, School of Medicine, Baltimore, MD; David Meyers, Johns Hopkins University, School of Medicine, Baltimore, MD; Philip A. Cole, Johns Hopkins University, School of Medicine, Baltimore, MD; Melanie Ott, Gladstone Institute, University of California, San Francisco, CA, University of California, San Francisco, CA; and Li Gan, Gladstone Institute, University of California, San Francisco, CA, University of California, San Francisco, CA.


Story Source:

The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.


Journal Reference:

  1. Sang-Won Min, Seo-Hyun Cho, Yungui Zhou, Sebastian Schroeder, Vahram Haroutunian, William W. Seeley, Eric J. Huang, Yong Shen, Eliezer Masliah, Chandrani Mukherjee, David Meyers, Philip A. Cole, Melanie Ott, Li Gan. Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy. Neuron, 2010; 67 (6): 953-966 DOI: 10.1016/j.neuron.2010.08.044

Cite This Page:

Cell Press. "Acetylation may contribute to dementia and Alzheimer's disease; May lead to new treatments." ScienceDaily. ScienceDaily, 23 September 2010. <www.sciencedaily.com/releases/2010/09/100922121939.htm>.
Cell Press. (2010, September 23). Acetylation may contribute to dementia and Alzheimer's disease; May lead to new treatments. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2010/09/100922121939.htm
Cell Press. "Acetylation may contribute to dementia and Alzheimer's disease; May lead to new treatments." ScienceDaily. www.sciencedaily.com/releases/2010/09/100922121939.htm (accessed July 31, 2014).

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