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Pathological and functional amyloid formation orchestrated by the secretory pathway
Mary E Huff1, William E Balch, Jeffery W Kelly
1The Scripps Research Institute, Departments of Chemistry, The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, BCC265, La Jolla, CA 92037, USA.
Current Opinion in Structural Biology
|December 17, 2003
Summary
Furin proteolysis initiates amyloidogenesis in both neurodegenerative diseases and functional melanosome formation. This process, combined with organelle changes, drives pathological and normal amyloid pathways.
Area of Science:
- Molecular Biology
- Neurodegenerative Diseases
- Cell Biology
Background:
- Amyloidogenesis is linked to neurodegenerative amyloid diseases.
- Proteolysis by furin is a key step in protein processing and secretion.
Purpose of the Study:
- To investigate the role of furin-mediated proteolysis in initiating amyloidogenesis.
- To explore the dual role of amyloidogenesis in both pathological and functional cellular processes.
Main Methods:
- Analysis of furin's role in variant gelsolin amyloidogenesis.
- Investigation of Pmel17 fiber formation and its necessity for melanosome biogenesis.
- Examination of organelle-specific environmental influences on amyloidogenesis.
Main Results:
- Furin proteolysis during secretion initiates variant gelsolin amyloidogenesis, linked to familial amyloidosis of Finnish type.
- Furin proteolysis also drives Pmel17 fiber formation, essential for functional melanosome biogenesis.
- Proteolysis and organelle environment changes together orchestrate both pathological and functional amyloidogenesis.
Conclusions:
- Furin-mediated proteolysis is a critical initiator of amyloidogenesis in diverse biological contexts.
- Amyloidogenesis is not solely pathological but also plays a role in essential cellular functions like melanosome formation.
- Understanding these pathways offers insights into neurodegenerative diseases and pigment cell biology.