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Introduction
Since the identification of Pten induced kinase 1 (PINK1) as a Parkinson's disease (PD) associated gene in 2004, a number of studies have sought to identify the biological roles of this serine/threonine kinase in order to aid therapeautic advances for the treatment of PD. PINK1 is a mitochondrially targeted serine/threonine kinase which has been shown to protect cells against oxidative stress induced apoptosis. Mutations associated with PD are located throughout the PINK1 protein but the majority are found within the kinase domain. The location of these mutations, including one that resides within the adenosine triphosphate (ATP) binding pocket of PINK1, suggests that loss of PINK1 kinase activity is responsible for disease initiation. In addition, mutations within the carboxy terminus of the protein have been shown to be important for optimal kinase activity. Table 1 lists all of the mutations identified within the pink1 gene and denotes their locations within the protein with respect to the kinase domain. The PINK1 protein is cleaved upon entry into the mitochondria to produce two protein fragments, one at 54 kDa (ΔN‐PINK1) and one at 45 kDa (ΔN2‐PINK1). Whether these cleavage products are released or exported from mitochondria after the cleavage event remains an area of current debate and the physiological relevance of cleavage is currently unknown. During the course of this review, we aim to look at the specific cellular roles assigned to PINK1 after 5 years of extensive study, summarize the evidence for each individual role and highlight areas still surrounded by controversy.
* mutation results in a stop codon.
⊗, ¥, ≠, Ø, #, ¶, ϕ = both mutations found in a compound heterozygous patient.
ï found in a compound heterozygote with mutation V317I.
# found in a compound heterozygote with mutation R492X.
¢ found in a compound heterozygote with mutation Q456*.
† mutation has been identified in patients and controls.
§ mutation was found in a control individual only.
‡ amino acid variant found in patients and controls which associates with late onset PD.
PINK1 protects cells against oxidative stress‐induced apoptosis
Oxidative stress and impaired electron transport chain function have been linked to the pathogenesis of PD, ever since exposure to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), a complex I inhibitor, was found to induce parkinsonism in humans (Langston...