Stress responses

PINK Participates in Parkinson’s Pathway

Science's STKE  13 Nov 2007:
Vol. 2007, Issue 412, pp. tw411
DOI: 10.1126/stke.4122007tw411

A neurodegenerative disease in mice with similarities to Parkinson’s disease in humans is caused by missense mutations in a serine protease known as HtrA2 (also called Omi). Plun-Favreau et al. describe a connection between this protein and PINK1, a mitochondrial protein kinase that is mutated in certain forms of Parkinson’s disease. HtrA2 functions to detect damaged or misfolded proteins caused by stress in the mitochondria. Misfolded proteins bind to a regulatory domain and activate the protease. The new work indicates that HtrA2 may also be regulated by phosphorylation in response to the stress-activated p38 MAP (mitogen-activated protein) kinase pathway. Although PINK1 binds to HtrA2 and was required for p38-activated phosphorylation and activation of HtrA2, PINK appeared not to directly phosphorylate HtrA2. Consistent with a role of this putative regulatory system in Parkinson’s disease, phosphorylation of HtrA2 was increased in samples of brain from patients with idiopathic Parkinson’s disease, as might be expected if mitochondrial stress in the diseased cells caused activation of the p38 pathway and consequent phosphorylation and activation of HtrA2. Commentary by Alnemri provides further context for the regulatory mechanism and its possible relevance to disease.

H. Plun-Favreau, K. Klupsch, N. Moisoi, S. Gandhi, S. Kjaer, D. Frith, K. Harvey, E. Deas, R. J. Harvey, N. McDonald, N. W. Wood, L. M. Martins, J. Downward, The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat. Cell Biol. 9, 1243-1252 (2007). [PubMed]

E. S. Alnemri, HtrA2 and Parkinson’s disease: Think PINK? Nat. Cell Biol. 9, 1227-1229 (2007). [PubMed]