Lecture 5: Protein Misfolding Diseases Flashcards
Prions
Proteinaceous infectious particle; only disease that is both infectious and genetic. Misfolded proteins propagate their conformation to normal proteins.
Types of prion disease
- Infectious
- Familial
- Sporadic
Features of PrP-Sc
-Only present in diseased brain
-Infectious
-Protease resistant
-Aggregated
-~65% beta sheets (compared to 3% normally)
-Amyloid structure; parallel, in-register beta sheets
Prion propagation specificity
Propagation is highly specific; i.e. species barrier due to conformational differences in normal PrP-C. Prion strains can even exist within a species.
“Prion-like” properties of other neurodegenerative diseases
-Seeded polymerization (in vitro)
-Transmission between cells (in culture)
-Seeding in vivo
-“Strains”
Pathological hallmarks of Alzheimer’s
- Extracellular A-beta neuritic plaques
- Intracellular P-tau neurofibrillary tangles
Amyloid cascade hypothesis
- Increased production/reduced clearance of A-beta peptide
- Hyperphosphorylation of tau and accumulation into Paired Helical Filaments (PHFs)
- Synaptic dysfunction and neuronal death
- Dementia
A-beta
Proteolytic fragment of Amyloid Precursor Protein
How is APP converted to A-beta?
- APP cleaved by beta-secretase
- beta-APP CTF cleaved by gamma secretase
- Amyloid-beta fragment remains
Where does gamma cleavage of APP occur?
Gamma cleavage can occur at multiple sites, creating A-beta pieces of varying lengths. Shorter is more benign, the longest (A-beta 42/43) are highly amyloidgenic
What genes mediate familial Alzheimer’s?
Mutations in APP favoring amyloidgenic peptides or in the gamma secretase complex (presenilin)
What kinds of genes are risk factors for sporadic Alzheimer’s?
Genes involved in microglia or inflammation, such as TREM2 and CD33
How does A-beta mAb therapy work?
mAb targeting A-beta helps to direct clearance of plaques, but show only modestly slower cognitive decline with major potential side effects
