Abstract
Mutations in the PTEN induced putative kinase 1 (PINK1) gene cause an autosomal recessive form of Parkinson disease (PD). So far, no substrates of PINK1 have been reported, and the mechanism by which PINK1 mutations lead to neurodegeneration is unknown. Here we report the identification of TNF receptor-associated protein 1 (TRAP1), a mitochondrial molecular chaperone also known as heat shock protein 75 (Hsp75), as a cellular substrate for PINK1 kinase. PINK1 binds and colocalizes with TRAP1 in the mitochondria and phosphorylates TRAP1 both in vitro and in vivo. We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. Moreover, we find that the ability of PINK1 to promote TRAP1 phosphorylation and cell survival is impaired by PD-linked PINK1 G309D, L347P, and W437X mutations. Our findings suggest a novel pathway by which PINK1 phosphorylates downstream effector TRAP1 to prevent oxidative-stress-induced apoptosis and implicate the dysregulation of this mitochondrial pathway in PD pathogenesis.
Highlights
Parkinson disease (PD) is the second most common neurodegenerative disease, characterized by the selective loss of dopaminergic neurons in the substantia nigra [1]
We find that PTEN induced putative kinase 1 (PINK1) normally protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria
The PINK1 mutations linked to PD impair the ability of PINK1 to phosphorylate TNF receptor-associated protein 1 (TRAP1) and promote cell survival
Summary
Parkinson disease (PD) is the second most common neurodegenerative disease, characterized by the selective loss of dopaminergic neurons in the substantia nigra [1]. The cause of PD, the sporadic disease, is unclear, but it likely involves both genetic and environmental factors. Genetic studies have identified a number of genes associated with familial PD [2]. Exposure to environmental toxins that inhibit the mitochondrial complex I can lead to PD-like phenotypes in animal models [4], suggesting the involvement of mitochondrial dysfunction in PD pathogenesis. Multiple additional types of PD-linked mutations or truncations in PINK1 have been reported, making PINK1 the second most common causative gene of recessive PD [6,7]. Despite autosomal recessive transmission of PINK1-linked early-onset PD, a number of heterozygous mutations affecting only one PINK1 allele have been associated with late-onset PD [6,7,8,9,10]. The pathogenic mechanisms by which PINK1 mutations lead to neurodegeneration are unknown
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