Pathogenic Signal Sequence Mutations in Progranulin Disrupt SRP Interactions Required for mRNA Stability

Area of Science:

• Molecular biology
• Cellular quality control mechanisms
• Neurodegenerative disease research

Background:

• Cells possess quality control pathways to prevent toxic protein accumulation.
• Regulation of Aberrant Protein Production (RAPP) degrades mRNA of aberrant secretory proteins during translation.
• Progranulin (GRN) haploinsufficiency is linked to frontotemporal lobar degeneration (FTLD).

Purpose of the Study:

• To identify endogenous substrates of the RAPP pathway.
• To investigate the role of FTLD-associated GRN mutations in RAPP activation.
• To elucidate the molecular mechanisms underlying GRN expression in FTLD.

Main Methods:

• Analysis of GRN mutations (W7R and A9D) and their interaction with signal recognition particle (SRP).
• Assessment of RAPP pathway activation in response to GRN variants.
• Monitoring of mRNA degradation and protein expression levels.

Main Results:

• FTLD-associated GRN mutations W7R and A9D disrupt co-translational interaction with SRP.
• This disruption triggers the RAPP pathway, leading to specific mRNA degradation.
• Wild-type GRN and the V5L polymorphism are expressed and secreted efficiently, without triggering RAPP.

Conclusions:

• RAPP is activated by specific FTLD-associated GRN mutations.
• The RAPP pathway contributes to the molecular pathology of A9D GRN and W7R GRN.
• Understanding RAPP's role in GRN expression offers insights into FTLD pathogenesis.