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The Serine Protease PARK13 Degrading Misfolded Parkinson's Disease Proteins And Confers Cellular Protection
Author(s) -
Basak Indranil,
Patil Ketan,
Larsen Jan Petter,
Møller Simon
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.894.6
Subject(s) - neuroprotection , serine protease , arabidopsis thaliana , microbiology and biotechnology , protease , autophagy , arabidopsis , alpha synuclein , unfolded protein response , cytosol , chemistry , biology , subcellular localization , neurodegeneration , parkinson's disease , biochemistry , enzyme , disease , gene , apoptosis , endoplasmic reticulum , mutant , medicine , pharmacology , cytoplasm , pathology
Mutations in HTRA2/Omi/PARK13 have been associated with Parkinson's disease (PD) and PARK13 show neuroprotective properties in mice. However, how PARK13 confers neuroprotection is largely unknown. We have developed Arabidopsis thaliana as a new multicellular and complementary plant model for studying PD‐associated proteins. We have shown that Arabidopsis AtPARK13, similar to human PARK13 (hPARK13), is a mitochondrial protease that confers thermotolerance. At elevated temperatures protein unfolding is more prevalent and we have demonstrated that unfolded casein acts as a better substrate for AtPARK13 as compared to native casein. Following these findings we showed that AtPARK13 is capable of degrading the PD proteins α‐synuclein (SNCA) and DJ‐1 with higher activity in response to their unfolded states. We also demonstrated that hPARK13 can degrade SNCA and clinical DJ‐1 mutated variants without autophagy involvement. We further investigated this phenomenon in neuroblastoma cells showing that monomeric SNCA is degraded by hPARK13. Interestingly, we further showed that higher order SNCA states are targets of cytosolic, membrane‐bound and nuclear hPARK13 suggesting that hPARK13 acts on different SNCA states depending on the subcellular localization. Our study not only suggests a new mechanism for PARK13 but also sheds light on its possible involvement in neurodegenerative diseases.