Summary: A new study reveals a critical gene network involved in Parkinson’s disease.
Source: University of Leicester.
“Studying the roles of genes such as ATF4 in human neurons could lead to tailored interventions that could one day prevent or delay the neuronal loss seen in Parkinson’s” – Dr Miguel Martins, MRC Toxicology Unit, University of Leicester.
A genetic ‘switch’ has been discovered by MRC researchers at the University of Leicester which could help to prevent or delay the symptoms of Parkinson’s disease.
In a paper published in the journal Cell Death and Differentiation, the team discovered that a gene called ATF4 plays a key role in Parkinson’s disease, acting as a ‘switch’ for genes that control mitochondrial metabolism for neuron health.
Dr Miguel Martins from the MRC Toxicology Unit at the University of Leicester, who led the research, explained: “When the expression of ATF4 is reduced in flies, expression of these mitochondrial genes drops. This drop results in dramatic locomotor defects, decreased lifespan, and dysfunctional mitochondria in the brain.
“Interestingly, when we overexpressed these mitochondrial genes in fly models of Parkinson’s, mitochondrial function was reestablished, and neuron loss was avoided.”
By discovering the gene networks that orchestrate this process, the researchers have singled out new therapeutic targets that could prevent neuron loss.
Some forms of Parkinson’s are caused by mutations in the genes PINK1 and PARKIN, which are instrumental in mitochondrial quality control.
Fruit flies with mutations in these genes accumulate defective mitochondria and exhibit Parkinson’s-like changes, including loss of neurons.
The researchers used PINK1 and PARKIN mutant flies to search for other critical Parkinson’s genes — and using a bioinformatics approach discovered that the ATF4 gene plays a key role.
Dr Martins added: “Studying the roles of these genes in human neurons could lead to tailored interventions that could one day prevent or delay the neuronal loss seen in Parkinson’s.”
The findings build upon recent research by the University of Leicester team, which recently discovered several genes that protect neurons in Parkinson’s disease, creating possibilities for new treatment options.
Two of the genes — PINK1 and PARKIN — affect how mitochondria break down amino acids to generate nucleotides – the metabolism of these molecules generates the energy that cells need to live.
About this Genetics research article
Dysfunctional mitochondrial metabolism has been linked to Parkinson’s and the team of researchers previously showed that boosting this metabolism with nucleotides can protect neurons.
Funding: The study was supported by Medical Research Council.
Source: Miguel Martins – University of Leicester Image Source: NeuroscienceNews.com image is in the public domain. Video Source: The video is credited to Research Square. Original Research: Full open access research for “dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective” by Ivana Celardo, Susann Lehmann, Ana C Costa, Samantha HY Loh & L Miguel Martins in Cell Death and Differentiation. Published online February 17 2017 doi:10.1038/cdd.2016.158
Cite This NeuroscienceNews.com Article
[cbtabs][cbtab title=”MLA”]University of Leicester “Discovery of Genetic Switch Could Help Prevent Parkinson’s Symptoms.” NeuroscienceNews. NeuroscienceNews, 17 February 2017. <https://neurosciencenews.com/parkinsons-genetics-neurology-6128/>.[/cbtab][cbtab title=”APA”]University of Leicester (2017, February 17). Discovery of Genetic Switch Could Help Prevent Parkinson’s Symptoms. NeuroscienceNew. Retrieved February 17, 2017 from https://neurosciencenews.com/parkinsons-genetics-neurology-6128/[/cbtab][cbtab title=”Chicago”]University of Leicester “Discovery of Genetic Switch Could Help Prevent Parkinson’s Symptoms.” https://neurosciencenews.com/parkinsons-genetics-neurology-6128/ (accessed February 17, 2017).[/cbtab][/cbtabs]
dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective
Neurons rely on mitochondria as their preferred source of energy. Mutations in PINK1 and PARKIN cause neuronal death in early-onset Parkinson’s disease (PD), thought to be due to mitochondrial dysfunction. In Drosophila pink1 and parkin mutants, mitochondrial defects lead to the compensatory upregulation of the mitochondrial one-carbon cycle metabolism genes by an unknown mechanism. Here we uncover that this branch is triggered by the activating transcription factor 4 (ATF4). We show that ATF4 regulates the expression of one-carbon metabolism genes SHMT2 and NMDMC as a protective response to mitochondrial toxicity. Suppressing Shmt2 or Nmdmc caused motor impairment and mitochondrial defects in flies. Epistatic analyses showed that suppressing the upregulation of Shmt2 or Nmdmc deteriorates the phenotype of pink1 or parkin mutants. Conversely, the genetic enhancement of these one-carbon metabolism genes in pink1 or parkin mutants was neuroprotective. We conclude that mitochondrial dysfunction caused by mutations in the Pink1/Parkin pathway engages ATF4-dependent activation of one-carbon metabolism as a protective response. Our findings show a central contribution of ATF4 signalling to PD that may represent a new therapeutic strategy.
“dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective” by Ivana Celardo, Susann Lehmann, Ana C Costa, Samantha HY Loh & L Miguel Martins in Cell Death and Differentiation. Published online February 17 2017 doi:10.1038/cdd.2016.158