Kinetic competition between the native state and a misfolded off-pathway intermediate may be common for large proteins with complex topologies

Mutation destabilises N more than I --> increased stability of I relative to N --> I more likely/longer lifetime (shifts equilibrium towards I)--> high risk of misfolding and aggregation

• Up-regulation of chaperones --> assist folding

• Translational attenuation --> reduced protein load

• Up-regulation of ERAD and autophagy --> removal of dnagerous unfolded proteins

BUT not present at all synaptic terminals (--> selective expression, targeting, and pathogenic vulnerability in certain neuronal populations) and expression also not confined to neurons (e.g. present in RBCs)

• This region also contains a NAC domain (residues 60–95) implicated in aggregation

• Most identified mutations associated with synucleinopathies are located in this region --> lipid binding or lack of may be associated with αS pathology

• Target of PTMs

• Interacts with proteins

• Modulates membrane-binding

• Protects against aggregation

Oligomeric intermediates are likely the most cytotoxic species and may permeabilise membranes (including mitochondrial membranes --> release of cytochrome C --> caspase activation --> apoptosis

• Mutations in PARK2, which encodes parkin --> accumulation of protein aggregates (including αS fibrils) and damaged mitochondria --> cellular damage --> early onset PD

• Parkin dysfunction leading to impaired mitophagy is especially detrimental in neurons due to their high energy needs

May accumulate within the nervous system of PD individuals bc. of an inflammatory/immune response

• Normally found in CNS neurons where it plays a crucial role in stabilizing microtubules in axons

• Mutations in MAPT on chromosome 17 (encodes tau) --> Alzheimer's (dysfunction in tau is sufficient to cause Alzheimers)

• Six tau isoforms of varying length (produced by alternate splicing) are expressed in the human brain

• Paired helical fibre (PHF) - filaments twist around each other like a double helix

• Straight fibre (SF) - straighter and slightly thicker

• Diseases other than Alzheimer's lack Aβ plaques

• 'Strain-like' properties: different diseases display different compositions of tau isoforms and have distinct filament morphologies

--> strain specificity e.g. sheep Scrapie has never infected humans

No nucleic acid involved in 'infection' - all disease information comes from the misfolded protein's ability to convert the normal protein into the pathogenic form

e.g. Familial CJD, fatal familial insomnia

ε4 --> increased risk of developing sporadic AD (especially if homozygous)

BUT not determinative (other factors involved)

Could affect oligomerization or clearance of Aβ and facilitates entry of some pathogens (e.g. HSV1) into the cell

Thr more polar than Ala --> disrupts hydrophobic cluster stabilising fibril --> may protect against AD

Val more hydrophobic than Ala --> strengthens hydrophobic interaction leading to fibril stability --> pathogenic

β- and γ-secretase cleavage --> amyloidgenic pathway

• 'LS' topology of individual subunits

  • N-terminus L-shaped

  • C-terminus S-shaped

• Staggered arrangement of non-planar subunits in a zipper-like manner

• Dimer interface shields hydrophobic C-termini from the solvent

• Different fibril ends ('groove' and 'ridge') with different binding pathways (and possibly energy barriers)

Strain-like properties: Aβ fibril polymorph may correlate with AD phenotype (e.g. rapidly progressive vs. prolonged-duration)

It is likely that AD prevention and treatment must also address the infection and inflammatory response that triggers Aβ production

• Likely mediated by pro-inflammatory cytokines TNF and IF-γ

Aβ may also stimulate inflammatory protein production by microglial cells and astrocytes --> positive feedback likely involved in mediating an inflammatory response

Aβ degradation mechanisms are often impaired in patients with AD

• Herpes viruses HSV1, HHV6 and HHV7 implicated in AD pathogenesis

• Opportunistic infection of commensal microbes (e.g. candida, chlamydia) implicated in AD pathogenesis

Associates with vesicle membranes through protein-membrane interactions and acts as a chaperone of SNARE complex assembly through protein-protein interactions

'Anticipation' - number of CAG repeats correlates with earlier disease onset and increased severity

These kinetic traps are not 'smoothed' by evolution bc. doing so would disrupt protein function

ε4 allele increases risk of developing Alzheimer's later in life BUT correlates with cognitive benefits early in life --> selected for!

• Young ε4 carriers have higher IQs than noncarriers

• ε4 carriers may recruit additional right hemisphere frontal regions in order to achieve cognitive advantage

• 25% of people carry the ε4 allele

ε4 allele increases risk of developing Alzheimer's later in life BUT correlates with cognitive benefits early in life --> selected for!

• Young ε4 carriers have higher IQs than noncarriers

• ε4 carriers may recruit additional right hemisphere frontal regions in order to achieve cognitive advantage

• 25% of people carry the ε4 allele