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A yeast model of optineurin proteinopathy reveals a unique aggregation pattern associated with cellular toxicity
Author(s) -
Kryndushkin Dmitry,
Ihrke Gudrun,
Piermartiri Tetsade C.,
Shewmaker Frank
Publication year - 2012
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.12075
Subject(s) - optineurin , biology , protein aggregation , yeast , amyotrophic lateral sclerosis , mutant , microbiology and biotechnology , toxicity , amyloid (mycology) , mutation , genetics , disease , gene , chemistry , medicine , organic chemistry , pathology , botany
Summary Many neurodegenerative diseases including amyotrophic lateral sclerosis ( ALS ) are linked to the accumulation of specific protein aggregates in affected regions of the nervous system. SOD1 , TDP‐43 , FUS and optineurin ( OPTN ) proteins were identified to form intraneuronal inclusions in ALS patients. In addition, mutations in OPTN are associated with both ALS and glaucoma. As the pathological role of OPTN in neuronal degeneration remains unresolved, we created a yeast model to study its potential for aggregation and toxicity. We observed that both wild type and disease‐associated mutants of OPTN form toxic non‐amyloid aggregates in yeast. Similar to reported cell culture and mouse models, the OPTN E 50 K mutant shows enhanced toxicity in yeast, implying a conserved gain‐of‐function mechanism. Furthermore, OPTN shows a unique aggregation pattern compared to other disease‐related proteins in yeast. OPTN aggregates colocalize only partially with the insoluble protein deposit ( IPOD ) site markers, but coincide perfectly with the prion seed‐reducing protein Btn2 and several other aggregation‐prone proteins, suggesting that protein aggregates are not limited to a single IPOD site. Importantly, changes in the B tn2p level modify OPTN toxicity and aggregation. This study generates a mechanistic framework for investigating how OPTN may trigger pathological changes in ALS and other OPTN ‐linked neurodegenerative disorders.