Disruption Of Proteostatic Networks In Alzheimer?s Disease | 21898
Journal of Alzheimers Disease & Parkinsonism
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The extracellular accumulation of ?-amyloid peptide is a key trigger in the pathogenesis of Alzheimer?s disease (AD) that
precedes the appearance of intracellular protein aggregate pathology formed by proteins such as Tau, ?-synuclein, and
TDP-43. These latter pathologies are potentially a consequence of diminished function of protein homeostatic machinery. We
developed a sequential detergent extraction method, followed by SDS-PAGE separation of the various fractions, in-gel trypsin
digestions, and LC-MS/MS proteomic approaches to identify proteins that lose solubility in the brains of APPswe/PS1dE9 (line
85) mice with high amyloid burden. This protocol was initially used in a study of two neural cell lines, SH-SY5Y neuroblastoma
and STTG-1 glioblastoma, that were exposed to mild heat-shock, leading to the identification of a number of cytosolic proteins
that rapidly lost solubility and could be viewed as being sensitive to disturbances in proteostasis. Using the same approach on
our APPswe/PS1dE9 model of Alzheimer amyloidosis, we identified numerous cytosolic proteins involved in glycolysis as well
as 14-3-3 proteins and other chaperones that show specific losses in solubility as amyloid accumulates. These data provide
in vivo evidence that the accumulation of extracellular amyloid can lead to diminished function of the intracellular protein
homeostasis network. Ongoing studies in culture cell models may provide additional insight into the mechanisms by which
amyloid disrupts proteostasis.
David R Borchelt has been with the University of Florida since April of 2005 after 13 years on the faculty of Johns Hopkins University School of Medicine. He has
authored, or co-authored, more than 100 research papers focusing on human neurodegenerative disorders. He gained his PhD from the University of Kentucky
in 1986, where he studied the viruses that are similar to the virus that causes AIDS. After receiving his doctorate, he worked as a post-doctoral fellow with Dr.
Stanley Prusiner at the University of California in San Francisco. In 1999, he won the Nobel Prize in Medicine for his work on infectious proteins that cause Mad
Cow disease, Cruetzfeldt-Jakob disease, and other neurodegenerative diseases of animals and humans. During his time with Dr. Prusiner, he produced some
of the seminal work on prion protein that supported this hypothesis. From this work, he began to realize that most human neurodegenerative diseases, including
amyotrophic lateral sclerosis, Huntington?s disease, and Alzheimer?s disease, share similarities with prion disease in that the symptoms and pathology are caused
by the accumulation of proteins in altered conformations.
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