Details

Autor(en) / Beteiligte

• Koh, Hyongjong
• Kim, Hyunjin
• Kim, Min Ju
• Park, Jeehye
• Lee, Hye-Jeong
• Chung, Jongkyeong

Titel

Silent Information Regulator 2 (Sir2) and Forkhead Box O (FOXO) Complement Mitochondrial Dysfunction and Dopaminergic Neuron Loss in Drosophila PTEN-induced Kinase 1 (PINK1) Null Mutant

Ist Teil von

• The Journal of biological chemistry, 2012-04, Vol.287 (16), p.12750-12758

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• PTEN-induced kinase 1 (PINK1), which is associated with early onset Parkinson disease, encodes a serine-threonine kinase that is critical for maintaining mitochondrial function. Moreover, another Parkinson disease-linked gene, parkin, functions downstream of PINK1 in protecting mitochondria and dopaminergic (DA) neuron. In our fly genetic screening, knockdown of Sir2 blocked PINK1 overexpression-induced phenotypes. Consistently, ectopic expression of Sir2 successfully rescued mitochondrial defects in PINK1 null mutants, but unexpectedly, failed in parkin mutants. In further genetic analyses, deletion of FOXO nullified the Sir2-induced mitochondrial restoration in PINK1 null mutants. Moreover, overexpression of FOXO or its downstream target gene such as SOD2 or Thor markedly ameliorated PINK1 loss-of-function defects, suggesting that FOXO mediates the mitochondrial protecting signal induced by Sir2. Consistent with its mitochondria-protecting role, Sir2 expression prevented the DA neuron loss of PINK1 null mutants in a FOXO-dependent manner. Loss of Sir2 or FOXO induced DA neuron degeneration, which is very similar to that of PINK1 null mutants. Furthermore, PINK1 deletion had no deleterious effect on the DA neuron loss in Sir2 or FOXO mutants, supporting the idea that Sir2, FOXO, and PINK1 protect DA neuron in a common pathway. Overall, these results strongly support the role of Sir2 and FOXO in preventing mitochondrial dysfunction and DA neuron loss, further suggesting that Sir2 and FOXO function downstream of PINK1 and independently of Parkin. Background:PINK1 loss of function induces mitochondrial dysfunction and dopaminergic neuron loss in Drosophila. Results: Sir2 shows a specific genetic interaction with PINK1 and rescues PINK1 null mutant phenotypes via FOXO. Conclusion: The strong genetic and functional interactions suggest that Sir2 and FOXO protect mitochondria and dopaminergic neuron downstream of PINK1. Significance: Understanding the molecular roles of PINK1 will be helpful for deciphering the molecular pathogenesis of Parkinson disease.