Protein Analysis - neurological disorders

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Neurological disorders often have a spectrum:

- suggesting different genetic basis and multiple genes

- many proteins can be implicated in a single disorder

- display variations in clinical severity and progression

Steady state of proteins = protein dynamics

Secreted primary protein - accumulates = alzheimers

*a mutation in the gene may result in a protein with an altered tertiary structure - misfolded proteins can cause a traffic jam in the translocation process

The Unfolded Protein Response (UPR)

protective but limited

can suppress expression of a protein

protein degredation pathways can help clear a protein

failure to deal with a misfolded protein can result in apoptosis

if detect unfolded, response switched on and slows down transcription rate of protein

UPR can help control the stress but if overloaded then it will clear protein away

Autophagy:

plays critical role in removing cell aggregates

help remove defective proteins or organelles by lysosomal action

Peliaeus-Merzbacher (PMD):

a defect in the gene for the myelin protein Plp1

delayed mental and physical development with severe neurological symptoms

rumpshaker is a model of PMD (C3H mutation) - several myelin proteins are reduced in rumpshaker

shaking pup is due to a mutation in the Plp1 gene

Plp protein sits across the fold of different membranes to tack down the myelin that is spiralling round to help connect different layers

*Western blotting uses antibodies to examine specific proteins

Plp endocytosis is accelerated in rumpshaker oligodendrocytes

Summary:

•Abnormal protein behaviour is common to many neurological disorders

•Specific genes may be mutated leading to aberrant specific proteins

•There are cellular pathways that can be activated to try an alleviate the burden of abnormal proteins

•Basic protein analysis methods such as pulse-chase can inform on the dynamics of a protein

•The protein is degraded more quickly in rumpshaker compared to wild type mice

•The rumpshaker mutant mouse is a model of a MILD form of PMD

•The UPR pathway is activated but declines as mice age

•Understanding the protein may help find a cure