More than 120 scientific presentations and 80 posters were offered at the fourth annual "Pep Talk: The Protein Information Week," held recently in San Diego. Presented by Cambridge Healthtech Institute, the conference provided exhibits, as well as sessions on protein folding disorders, protein arrays, protein expression, protein process development, the human proteome, and protein therapeutics.
Because recent discoveries have shown that the misfolding or aggregation of proteins is responsible for many of the most devastating diseases of the 21st century, including Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob Disease, cystic fibrosis, type 2 diabetes, and even some cancers, a two-day segment of the Pep Talk program was devoted to protein folding disorders.
Experts provided insights into strategies for elucidating protein misfolding and aggregation mechanisms, methods for improved study of these events and strategies for effective drug discovery and development for these disorders.
It has been extremely difficult to study the changes that result in these pathologies because of the speed of folding and the limited differences between properly and misfolded proteins, according to the speakers.
Mechanism of TSEs
"Understanding the mechanisms of transmissible spongiform encephalopathies (TSEs) is the bridge to understanding Alzheimer's disease," said Abraham Grossman, Ph.D., president and CSO of Q-RNA (New York City), who described the ways in which research with prion chaperones or facilitators has revealed commonalities among misfolded protein diseases.
Using an in vitro system called Tripartite, Q-RNA demonstrated that a genetically engineered RNA chaperone induces amyloid formation. The company is using its technology to develop systems for target identification, drug discovery, and multifaceted validation to enable the development of effective drugs for Alzheimer's disease and other protein folding disorders.
TSEs are characterized by accumulation of insoluble deposits composed of amyloidogenic prion protein (PrP) in animals and other disease specific proteins in human diseases, according to Dr. Grossman.
The transition of PrP proteins from the native state to its aggregated conformation and accumulation of PrP is considered to be a multistep process that involves participation of various cellular chaperones or facilitators.
An RNA and a non-nucleic acid serum component have been identified as chaperone facilitators that participate in PrP misfolding and aggregation. Dr. Grossman believes that the identified chaperones and their cellular counterparts represent targets for development of new therapeutics against TSE and other misfolded protein diseases.
Susan Catalano, Ph.D., director of discovery biology at Acumen Pharmaceuticals (S. San Francisco) discussed amyloid-beta-derived diffusible ligands (ADDLs), proteins that exhibit neurotoxic activity and cause synaptic failure. Acumen is developing disease-modifying drugs targeting soluble oligomers of amyloid beta 1-42 in Alzheimer's disease and other memory-related disorders.
Dr. Catalano explained that ADDLs are elevated in the brains of Alzheimer's patients, ADDLs affect memory-related signaling, ADDL levels correlate with memory deficits, and injected ADDLs disrupt memory.
Acumen has discovered that specific antibodies block toxicity caused by ADDLs and stop ADDLs from binding. One such antibody recognizes ADDLs and stops memory deficits in mice.