Lecture neurodegenerative disorders 1: general mechanisms Flashcards
How are protein aggregates formed?
An unfolded native monomer that won’t fold can form β-sheets in the nucleus. These sheets are very sticky and will stick together to form protein aggregates.
Protein aggregation leads to two things. What two things?
- Loss of function
- Gain of toxic function
Answer the following questions:
- Where in the cell are proteins synthesized?
- What needs to happen after proteins have been synthesized?
- In the cytosol
- Synthesized proteins are still in their native unfolded form and need to be folded in a functional conformation. The proteins are therefore translocated to the endoplasmatic reticulum (ER).
⅓ of proteins still misfold in the ER. What solution is there to this?
Protein quality control system by chaperones (e.g. heat-shock proteins). These proteins recognize misfolded proteins and will try to fold the protein in the correct way by keeping proteins in a folding-competent state.
Some heat-shock proteins (HSPs) are ATP dependent and some are not. Name three ATP dependent Hsps and one ATP independent Hsp.
- ATP dependent → Hsp90, Hsp70, Hsp60
- ATP independent → Small Hsp
How does Hsp70 refold misfolded proteins?
Hsp70 has a closed and open conformation. In open conformation, ATP is bound and the substrate-binding domain is exposed so that Hsp70 can bind misfolded proteins. So in its active form, Hsp70 binds a misfolded protein. Next, ATP is hydrolyzed to ADP and the conformation changes to a closed one. The misfolded protein is now ‘trapped’ in the Hsp70 conformation and the protein is refolded. At last, ADP is exchanged for ATP, where the conformation opens and the refolded protein is released.
Thus, binding and release of the unfolded protein is dependent on ATP and a co-chaperone.
What happens when refolding of a misfolded protein fails?
The protein is tagged for degradation by an ubiquitin tag.
Describe the Ubiquitin-Proteasome System (UPS).
This system is meant for monomeric (misfolded) proteins, where these proteins are tagged by a polyubiquitin chain. This chain is recognized by the proteasome for degradation. The proteasome has a cilindric shape with on the inside catalytic activity. The ubiqtuitin tagged protein is moved through the proteasome and gets degraded.
So what happens when you inhibit the proteasome?
It induces accumulation of polyubiquitin-tagged proteins, as can also be seen in the picture.
Another protein-degradation system is autophagy. Describe autophagy.
Autophagy is protein degradation for protein aggregates or other large molecules, like organelles. Here, a double membrane is formed around the molecule targetted for degradation and lysosomes fuse with it, forming an autolysosome. Lysosomes have proteolytic activity that cause the molecule to be broken down.
There are 4 different types of protein conformations that can be targetted for degradation: native, misfolded monomer, oligomer or fibril.
- Describe for each if they can be degraded by proteasome, autophagy or inclusion body.
- Native conformation, can be degraded by the proteasome
- Misfolded monomer, can be degraded by the proteasome or autophagy.
- Oligomer, can be degraded by autophagy or inclusion body.
- Fibril, can be degraded by inclusion body.
Name the three causes (aetiology) of neurodegenartive diseases.
- Sporadic
- Acquired
- Genetic
Huntington’s disease
- What is the aetiology?
- What protein aggregates are causative of the disease?
- What brain region is affected?
- What is a typical symptom for Huntington’s?
- Aetiology: genetic
- Aggregates: Huntingtin protein
- Brain region: basal ganglia
- Symptom: chorea (unpredictable and/or uncontrollable movement)
How does Huntington’s disease occur?
The Huntingtin gene is responsible for the disease. The Huntingtin gene is normally composed of a CAG-triplet with a repeat expansion of 10-26 times. In Huntington’s disease, this repeat expansion is about 37-80 repeats long. This results in protein aggregation of the Huntingtin protein.
Is fibril formation and disease connected?
Yes, definitely. Only quantitatively not → there can be many deposits but little or no disease and there can be little or nog deposits but severe disease.