How Genetics & Environment Likely Cause of Parkinson’s Detailed

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Using a roundworm animal model, researchers identified a crucial mechanism for how signals from the environment can be combined with genetic susceptibility to influence the development of Parkinson’s disease.

Mutations in the TNK2 gene, which have been reported in people with familial Parkinson’s, were found to lead to neurodegeneration by changing both dopaminergic and epigenetic signaling.

Dopamine is the brain chemical messenger progressively lost in Parkinson’s, while epigenetics refers to chemical modifications in DNA that can turn genes on or off without altering the actual DNA sequence. Epigenetic processes can be viewed as a mediator between genes and the environment.

“This is not instantly a magic bullet, but this work tells us a lot about new possibilities for therapies,” Guy Caldwell, PhD, the study’s senior author and a professor of biological sciences at the University of Alabama, said in a university press release.

“We showed solid evidence on how this combination genetic-and-environmental mechanism influences neurodegeneration,” Caldwell added. “How to exploit it is the next area of discovery.”

Genetic variants, environment manifest as changes in gene activity

The discovery was in the study “Integrated regulation of dopaminergic and epigenetic effectors of neuroprotection in Parkinson’s disease models,” published in the Proceedings of the National Academy of Sciences.

Parkinson’s symptoms arise from the progressive loss of dopaminergic, or dopamine-producing, neurons. Disease susceptibility appears to be due to genetic predisposition and environmental factors, “often manifesting as changes in gene [activity] that are coordinately controlled by small RNA molecules,” the researchers wrote.

Large-scale genetic analysis has found variants in the TNK2 gene, which provides instructions to produce an enzyme called tyrosine nonreceptor kinase-2 (TNK2), in people with familial Parkinson’s.

TNK2 (also called ACK1) is produced at high levels in synapses, the junctions between neurons where chemical messengers like dopamine are released to facilitate cell-to-cell communication.

Here, TNK2 specifically interacts with the dopamine transporter (DaT), a protein that pumps dopamine out of the synapse back into the cell, thereby directly modulating dopamine reuptake from the synapse.

TNK2’s production, in turn, is regulated by NEDD4, an enzyme that marks TNK2 for degradation. Previous studies demonstrated that NAB2, a small molecule that activates NEDD4, strongly protected against neurodegeneration across multiple Parkinson’s models, including patients-derived neurons.

Based on these findings, Caldwell and colleagues hypothesized that Parkinson’s-associated TNK2 variants prevent the TNK2 enzyme’s degradation by NEDD4. This could result in the abnormal regulation of DaT and, ultimately, in increased dopamine reuptake, which weakens synaptic dopaminergic signaling and can be toxic to neurons.

To test this, the researchers used Caenorhabditis elegans, or C. elegans, a tiny, transparent roundworm that shares about half its genes with humans. These worms are a validated, low-cost model used to rapidly investigate a range of neurological diseases.

In C. elegans, TNK2’s equivalent is called SID-3. Unlike TNK2, SID-3 modulates epigenetic signaling by controlling the cellular entry of small RNA molecules, such as microRNAs, that ultimately silence the activity of other genes in response to environmental changes.

“We hypothesized that TNK2/SID-3 represents a node of integrated dopaminergic and epigenetic signaling essential to neuronal [healthy balance],” the team wrote.

Worms lacking SID-3 showed reduced dopaminergic neuron uptake of 6-hydroxydopamine (6-OHDA), a chemical selectively toxic to dopaminergic neurons and whose uptake by cells also is dependent on DaT.

This provided evidence for functional similarities between the human and worm proteins in dopamine transporter modulation.

Similarly, treating normal worms with either a TNK2 blocker or the NEDD4-activator NAB2 significantly protected the worms from 6-OHDA-induced neurotoxicity and neurodegeneration.

Findings in worms extended to rat neurons grown in lab

To show that these results can be extended to mammals, the researchers treated lab-grown rat neurons with NAB2 to activate NEDD4. Its use led to a drop in TNK2 levels and attenuated 6-OHDA-induced neurotoxicity, the team reported.

In addition, worms carrying SID-3 mutations matching the TNK2 mutations found in Parkinson’s patients were more susceptible to dopaminergic neuron loss. They also showed more pronounced RNA molecule-mediated gene silencing in dopaminergic neurons, which enhanced susceptibility to neurodegeneration.

“Dopamine is tightly regulated within the body, and a little tweak of dopamine levels can have a profound impact,” Caldwell said. “By engineering worms to mimic the patient mutations, we clarified that the TNK2 protein is staying on [active] too long.”

Overall, TNK2 mutations in Parkinson’s may lead to a reduction in synaptic dopamine, as well as the RNA molecule-mediated suppression of genes involved in pathways required to maintain dopamine balance. This supports the TNK2 enzyme as a sort of “dial,” turning up or down the activity of certain genes.

“The ‘dial’ is not responding to being turned [off] and is not behaving like it should be, and that imbalance leads to neurodegeneration,” Caldwell added.

“This research reveals a functional convergence of proteins that modulate uptake of both dopamine and small RNAs, as a regulatory intersection for the integrated control of dopaminergic neuron health,” the researchers wrote.

This preclinical study also “shows how we can use a system like worms to decipher the meaning of genetic variations in humans,” Caldwell said.

“With the growing informational overload of human DNA sequencing data that exists, parsing ‘the music within the noise’ is essential for the proper interpretation of the many differences between all of us,” he added.

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