Abstract

In mice, targeted deletion of the serine protease HtrA2 (also known as Omi) causes mitochondrial dysfunction leading to a neurodegenerative disorder with parkinsonian features. In humans, point mutations in HtrA2 are a susceptibility factor for Parkinson's disease (PARK13 locus). Mutations in PINK1, a putative mitochondrial protein kinase, are associated with the PARK6 autosomal recessive locus for susceptibility to early-onset Parkinson's disease. Here we determine that HtrA2 interacts with PINK1 and that both are components of the same stress-sensing pathway. HtrA2 is phosphorylated on activation of the p38 pathway, occurring in a PINK1-dependent manner at a residue adjacent to a position found mutated in patients with Parkinson's disease. HtrA2 phosphorylation is decreased in brains of patients with Parkinson's disease carrying mutations in PINK1. We suggest that PINK1-dependent phosphorylation of HtrA2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress.

1. Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
2. Structural Biology, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
3. Protein Analysis Laboratories, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
4. Cell Death Regulation Laboratory, MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
5. Department of Molecular Neuroscience, Institute of Neurology, and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
6. Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AX, UK.
7. These authors contributed equally to this work.

Correspondence to: L. Miguel Martins⁴ e-mail: lmm24@leicester.ac.uk

Correspondence to: Julian Downward¹ e-mail: julian.downward@cancer.org.uk

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