Cell 154, 737–747 (2013)

Credit: AMANDINE BERTHET

Parkinson's disease (PD) is a progressive neurological disorder in which the substantia nigra region of the brain is depleted in dopaminergic neurons. Mitochondrial defects have long been associated with PD. For example, mutations in PTEN-induced kinase 1 (PINK1), which is involved in mitochondrial maintenance in neurons, have been linked to an early-onset form of PD, prompting suggestions that enhancers of PINK1 activity could be neuroprotective. Hertz et al. now identify a nucleotide triphosphate 'neo-substrate' that elevates PINK1 activity in neurons and provide cellular data in support of this therapeutic model. Examination of PINK1 sequences, particularly of the G309D mutant associated with PD, led the authors to hypothesize that PINK1 enzymes may be able to accommodate larger ATP analogs as substrates. A screen of a small panel of N6-alkyl-ATP analogs revealed that PINK1 and its G309D mutant use the neo-substrate kinetin triphosphate (KTP, N6-furfuryl ATP) more efficiently than ATP itself. Cells treated with kinetin, the nucleoside precursor of KTP, readily accumulate KTP at amounts that restore nearly wild-type activity of PINK1. Finally, the authors showed that neurons treated with kinetin display several molecular phenotypes consistent with PINK1 activation. In addition to validating a potential therapeutic avenue for early-onset PD, the study points toward the possibility that neo-substrate activation could be a general approach for modulating disease-related kinase activity.