Proteinopathies in neurodegenerative diseases alpha-Synuclein aggregation models of Parkinson’s disease Flashcards
What is proteinopathy? (Also proteopathy)
- ## Class of diseases where certain proteins become structurally abnormal, and disrupt the function of cells.
What diseases is proteopathy involved with, for example?
More than 20 degenerative conditions are involved. Alzheimer’s Disease, Type II diabetes, etc.
What is an example of proteopathy related to protein folding?
When proteins misfold, they can become toxic in some way. They can gain a toxic function, or lose their normal function.
What is amyloid?
Any of a number of complex proteins that are deposited in tissues and that share selected laboratory features such as a change in the fluorescence intensity of certain aromatic dyes like Congo Red.
Tell a little about amyloid disorders.
Amyloids are present in many diseases. Each amyloid disorder arises from a particular misfolded protein or peptide.
How do misfolded proteins work in cells?
- They exist there together with unfolded, intermediately folded, and correctly folded species.
- In healthy cells, misfolded proteins are either degraded or refolded correctly by chaperone proteins that are involved in protein folding.
- It is believed that many peptides and proteins with no connection to disease can form amyloid fibrils under appropriate biochemical conditions.
- Higher order amyloid aggregates are highly resistant to degradation.
Are amyloids always bad?
No. Some amyloid fibrils that form naturally under nonpathological conditions have functional roles in living systems.
How do misfolded disease proteins disrupt the central nervous system functionality?
The mechanism differs depending on the protein species, but generally in neurodegenerative disease, they produce synaptic dysfunction and ultimately neuronal cell death.
What are common toxicity mechanisms of misfolded proteins?
1) Calcium signaling abnormalities
2) Mitochondrial dysfunction
3) Oxidative stress
4) Neuroinflammation
What can aggregates of misfolded proteins do to disrupt the nervous system?
1) Exert toxic effects by aberrant interactions with other cytosolic proteins
2) Engage in and disrupt the cellular stress responses and disrupt proteostasis
What is a proteostatic collapse?
A vicious cycle of protein aggregation. Some proteins may cause oxidative stress in neurons, and this stress promotes the aggregation of these proteins. This can lead to a proteostatic collapse.
What helps maintain proteostasis?
Chaperone proteins. They can unfold and refold misfolded proteins or target them for degradation.
There are over 300 chaperones identified in the human proteome.
Progressive failures of proteostasis network occurs with aging.
Why is therapeutic targeting of protein misfolding hard?
1) UNCERTAINTY. We don’t know which forms of each proteins are responsible for cellular toxicity.
2) MODELS. The models for disease states in vivo and in vitro are limited.
3) LIMITED UNDERSTANDING. We don’t know which components of the cellular proteostatic machinery each of the disease proteins interact with.
Talk about targeting chaperones when it comes to protein misfolding.
- Chaperones are involved in all aspects of proteostasis.
- Variety and cell-type selectivity provide opportunities but also challenges.
- Over 20 different chaperones have been found to confer neuroprotection when over-expressed in cell or animal models of neurodegenerative diseases.
- One idea: Develop small molecule inhibitors or activators of specific chaperones.
Talk about targeting degradation when it comes to protein misfolding.
- Choosing promising targets from proteosome/autophagy pathways is hard: 500-1000 proteins involved just with the proteosome system
- For most diseases, we don’t know which form(s) of the disease protein are primarily responsible
- Some small mole cules that promote disease protein degradation have been found in cultured cells, but not successful in in vivo models
