Neurodegeneration Exploring Commonalities Across Diseases: Workshop Summary (2013) / Chapter Skim
Currently Skimming:
3 Protein Aggregation
3 Protein Aggregation
Pages 23-32
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 23... ...
• Therapies that stimulate the cell's normal clearance mecha nisms are likely to show promise for treating neurodegenera tive disease, as are therapies that prevent protein aggregation in the first place. Protein misfolding and other errors in protein generation occur frequently within cells, and the cell has evolved a range of mechanisms to ensure proper folding and to eliminate aggregated or otherwise damaged 23
|
From page 24... ...
Because protein aggregation is common across many neurodegenerative diseases, these therapeutic approaches might benefit more than one disease. Proteostasis Proteostasis, or protein homeostasis, is the collective term used to describe a variety of cellular processes designed to minimize damage from altered, misfolded, and otherwise damaged proteins.
|
From page 25... ...
Proteasomes One significant component of the proteostasis network is carried out by proteasomes, multisubunit complexes within the nucleus and cytoplasm that degrade soluble protein, according to Alfred Goldberg of Harvard Medical School. The vast majority of damaged proteins are normally degraded by proteasomes, and so too are smaller protein aggregates.
|
From page 26... ...
(1) In the optimal state, molecular chaperones, clearance mechanisms, and detoxifying enzymes keep in check mutations, biosynthetic errors, energy deficits, and protein damage.
|
From page 27... ...
. He observed that deubiquitinating enzymes are more amenable to drug targeting than are the ubiquitin ligases because they are cysteine proteases, which have a defined mechanism of action and highly specific targets.
|
From page 28... ...
This was found to be the case in a study of Huntington's disease, according to Ana Maria Cuervo of Albert Einstein School of Medicine. In mouse models of Huntington's disease and cells from Huntington's patients, autophagosomes failed to efficiently trap protein deposits, organelles, and other cargo (Martinez-Vicente et al., 2010)
|
From page 29... ...
Hetz emphasized that the contribution of the UPR pathway to neurodegenerative diseases is not fully understood, including the circumstances under which it appears to provide an adaptive response that increases survival of neurons, as well as the circumstances under which it represents a pathological mechanism that leads to neuronal dysfunction or cell death when the damage is too high. Hetz and his collaborators have been working to further understand the role of UPR in neurodegenerative disease by generating new mouse models that enable them to manipulate the UPR and
|
From page 30... ...
may even inhibit the death of neurons by promoting autophagy, suggesting that preconditioning could have potential value in developing therapies for neurodegenerative diseases (Fouillet et al., 2012)
|
From page 31... ...
(Dunlop, Ommaya) • Study whether people with neurodegenerative disease have genetic susceptibility to protein overexpression or misfolding.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.