lecture 3: Protein Folding, CTE, and Alzheimers

describe the two models of protein misfolding?

hierarchical model: concept that protein structure progressively builds up from secondary structures, which then assemble into tertiary structures, and then quaternary structures. disruption at any level can lead to protein misfolding and potential disease states.

molten globule model: a partially folded protein state that acts as a intermediate during protein folding, where the protein has some secondary structure elements but lacks the tightly packed tertiary structure, making it a “melting pot” for conformational changes and susceptible to misfolding if not guided properly towards native state. forms clumps

describe why is there the need for protein chaperones?

a) what do they do?

b) what energy source do they use?

c) how can they buffer against mutations?

a) PFC sequester the protein (isolates proteins and prevents it from binding other proteins) and allows it to refold. Sometimes it undergoes many rounds of refolding. Process of binding misfolded proteins and sequestering it requires energy.

b) ATP hydrolysis

c) they actively assist misfolded proteins, caused by mutations, to fold into their correct functional conformation

how do chaperones buffer genetic changes and what happens in stressful conditions?

can buffer genetic changes under stressful conditions the chamber is full and on not fold correctly so it buffers the genetic mutations so that the protein cant fold correctly and that prevents the mutation from forming because the protein cant fold.

what protein are misfolded in Alzheimer’s disease

beta amyloid

what secondary structure leads to the pathology

beta sheet

why are misfolded proteins toxic to the cell

can disrupt normal cellular function by aggregating together, forming clumps that interfere with the operation of cellular interactions

how does traumatic brain injury speed up the process

brain trauma speeds up hydrolysis which is the process in which polypeptides are converted back to amino acids. b amyloid more sticky

what is the mutation that leads to more susceptibility to Alzheimers

changes in amino acids in the B-APP protein

how are therapies being developed to prevent Alzheimers?

drug therapies that prevent protein aggregation, immunotherapy to clear amyloid beta plaques

describe how prions form and how they are spread

prions form when a normal protein in the body called prion protein misfolds into an abnormal shape, which then acts as a template to convert other normal proteins into the same misfolded structure, leading to a chain reaction that accumulates these abnormal proteins in the brain, causing disease. they are spread through direct contact with infected tissue, typically ingestion of contaminated meat from infected animals or through medical procedures involving contaminated instruments. (PrPC goes to PrPrsc)