Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson’s disease

Abstract

Mutations in PINK1 cause early-onset Parkinson's disease (PD). Studies in Drosophila melanogaster have highlighted mitochondrial dysfunction on loss of Pink1 as a central mechanism of PD pathogenesis. Here we show that global analysis of transcriptional changes in Drosophila pink1 mutants reveals an upregulation of genes involved in nucleotide metabolism, critical for neuronal mitochondrial DNA synthesis. These key transcriptional changes were also detected in brains of PD patients harbouring PINK1 mutations. We demonstrate that genetic enhancement of the nucleotide salvage pathway in neurons of pink1 mutant flies rescues mitochondrial impairment. In addition, pharmacological approaches enhancing nucleotide pools reduce mitochondrial dysfunction caused by Pink1 deficiency. We conclude that loss of Pink1 evokes the activation of a previously unidentified metabolic reprogramming pathway to increase nucleotide pools and promote mitochondrial biogenesis. We propose that targeting strategies enhancing nucleotide synthesis pathways may reverse mitochondrial dysfunction and rescue neurodegeneration in PD and, potentially, other diseases linked to mitochondrial impairment.The role of mitochondrial impairment in PD has long been debated. Recently, the identification of causative mutations in PINK1, a gene encoding a mitochondrial kinase in PD patients has renewed interest in the role of mitochondrial damage in PD (ref. 1).

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

“…Metabolic profiles were obtained for each individual genotype using the Metabolon Platform (Metabolon), as described in ref. 47. Processing of each sample (six KO and five WT samples) was conducted using a proprietary series of organic and aqueous extractions to remove the protein fraction while allowing maximum recovery of small molecules.…”

Mitochondrial retrograde signaling regulates neuronal function

“…Impl3 expression is significantly increased in tko mutant flies, pink1 mutant flies, and cytochrome c oxidase Va (CoVa) knock-down S2 cells, while Thor expression is significantly increased in the latter two models (Dataset S4) (19)(20)(21). Overall, although different tissues were used, 31 genes were commonly regulated in our gene set and at least one of the other three studies (Dataset S4).…”

Folinic acid is neuroprotective in a fly model of Parkinson’s disease associated with <em>pink1</em> mutations

“…1A). The incidence of this crushed thorax in pink1 mutants flies was reported to be significantly decreased by maintaining these flies in a FA-supplemented diet beginning at early embryogenesis [7]. We first evaluated whether FiA can also suppress the crushed thorax phenotype in pink1 mutants.…”

“…We next investigated whether both FA and FiA could suppress this neurodegeneration. pink1 mutant flies fed on FA since embryonic development are protected from the loss of PPL1 cluster neuronsA [7]. We therefore tested whether an FiA-supplemented diet was also neuroprotective.…”

“…This invertebrate is also an excellent in vivo platform for testing chemicals with therapeutic potential (reviewed in [5]). Drosophila pink1 mutants show an age dependent loss of dopaminergic neurons [6] that can be blocked via an FA-supplemented diet beginning at early embryogenesis [7]. In humans, FA is generally well absorbed, but the conversion of FA to its metabolically active coenzyme forms is complex (reviewed in [8]).…”