Summary: Study reveals how cues from the environment integrate with genetic information that influences neuronal survival and health, providing new insights into how Parkinson’s disease can develop. The results reveal that mutations in the TNK2 gene lead to the degeneration of dopamine-producing neurons, leading to the pathology of Parkinson’s disease.
Source: University of Alabama
University of Alabama researchers have identified a critical mechanism of how cues from the environment are integrated with genetic information to influence brain cell health and survival, providing key insight into disease development of Parkinson’s.
In the findings described in an article recently published in the Proceedings of the National Academy of Sciencesresearchers are opening up unexplored treatment pathways that could highlight how regulating forces outside the body helps protect brain cells, or neurons.
“It’s not instantly a magic bullet, but this work tells us a lot about new possibilities for therapies,” said Dr. Guy Caldwell, a university research professor emeritus in biological sciences, whose lab led the research.
“We have shown strong evidence for how this combination of genetic and environmental mechanisms influences neurodegeneration, but how to harness it is the next area of discovery.”
Currently, no cure or treatment exists to prevent or stop this disease, which affects more than 10 million people worldwide, with more than 60,000 Americans diagnosed each year. The recent study examined the neurons that produce the chemical dopamine.
The progressive death of dopaminergic neurons underlies the onset and symptoms commonly associated with Parkinson’s disease, such as involuntary tremors and jerks. By the time a patient with Parkinson’s disease begins to show symptoms of the disease, they have probably lost up to 50-80% of the dopamine neurons in their body.
This new research shows how a specific protein in the body, TNK2, acts as a sort of dial, increasing or decreasing the use of certain genes, effectively adjusting dopamine levels to optimize neuron function and survival. In contrast, mutations in the human TNK2 gene lead to the degeneration of dopamine-producing neurons, leading to Parkinson’s disease.
Caldwell, Dr. Kim Caldwell, professor of biological sciences, and Dr. Han-A Park, assistant professor of human nutrition, and six UA students co-authored the article in PNAS.
The Caldwells’ lab received funding from the National Institutes of Health to identify the molecular factors that determine whether an individual is resilient or susceptible to dopamine neuron degeneration. Research focuses on epigenetics, the study of mechanisms that turn genes on and off in response to external environmental stressors.
UA researchers report the discovery of an intersection where the control of dopamine levels and the regulation of the epigenetic response meet to confer their combined impact on neuronal health. Given the variety of important biological functions and behaviors involving dopamine, the implications of this research include potential ways to influence a wide range of conditions, from depression and schizophrenia to drug addiction and Parkinson’s disease. .
For this study, researchers altered the genes of tiny roundworms known as C. elegans, mimicking mutations found in patients. Worms share about half their genes with humans, and their core characteristics allow for inexpensive and rapid experimentation for a range of neurological diseases. UA researchers can induce Parkinson-like effects in the worm’s dopaminergic neurons, as a proxy for testing neuron loss in the human brain as part of the disease.
Previous discoveries using Caldwell’s worm models have repeatedly led to later validated results in human research, and the study discussed in the article is another strong endorsement of the worm as a preclinical model for worm research. neurodegenerative diseases.
“This research shows how we can use a system like worms to decipher the significance of genetic variation in humans,” Caldwell said. “With the growing information overload of human DNA sequencing data that exists, the analysis of ‘music in noise’ is essential for the proper interpretation of the many differences between us all.”
Although the worm’s version of human TNK2, named SID-3, is slightly different, it controls dopamine levels in worms the same way TNK2 does in humans. The human protein TNK2 is known to help supply and recycle dopamine in neurons, while SID-3 in worms is known to regulate the transport of extracts of a type of small, mobile double-stranded RNA molecules called microRNAs that act in response to the environment. changes and determine if genes are expressed.
When the TNK2 protein is mutated, as in patients with Parkinson’s disease, it delivers excess microRNA, permanently suppressing genes that normally maintain dopamine balance in dopamine neurons. It also results in TNK2 simultaneously recycling too much dopamine, removing dopamine from the space between neurons, called the synapse, where it is needed.
This combination of synaptic dopamine depletion, while suppressing genes involved in neuroprotection, explains why patients with TNK2 mutations present with Parkinson’s disease. The study directly demonstrated that the mutated protein remains active for too long, depriving neurons of the dopamine balance necessary for normal functioning.
“Dopamine is tightly regulated in the body, and a small adjustment in dopamine levels can have a profound impact. By designing worms to mimic patient mutations, we clarified that the TNK2 protein hangs around too long,” Caldwell said. “The ‘dial’ does not respond to rotation and does not behave as it should, and this imbalance leads to neurodegeneration.”
Park, an assistant professor of human nutrition, and his student, Madison Scott, showed that the same mechanism for regulating TNK2 levels was present in neurons cultured in the lab from rats. This extended the significance of the worm finds to mammals and portends that future research will be fruitful.
Along with professors Guy and Kim Caldwell and Park, other co-authors of the paper include recent UA graduate students Brucker Nourse and Shannon Russell, former UA undergraduate students Nathan Moniz and Madison Scott , as well as current undergraduates Kylie Peter and Lena Seyfarth.
About this Parkinson’s disease research news
Author: adam jones
Source: University of Alabama
Contact: Adam Jones – University of Alabama
Picture: Image is in public domain
Original research: Access closed.
“Integrated regulation of dopaminergic and epigenetic effectors of neuroprotection in models of Parkinson’s disease” by Guy Caldwell et al. PNAS
Integrated regulation of dopaminergic and epigenetic effectors of neuroprotection in models of Parkinson’s disease
Whole-exome DNA sequencing of a patient with Parkinson’s disease (PD) identified single nucleotide polymorphisms (SNPs) in the non-receptor tyrosine kinase-2 (TNK2) embarrassed.
Although this kinase has previously demonstrated activity in preventing dopamine reuptake transporter (DAT) endocytosis, a causal role for TNK2-associated dysfunction in PD remains unresolved.
We postulated dopaminergic neurodegeneration resulting from patient-associated variants in TNK2 were the consequence of an aberrant or prolonged overactivity of TNK2, the latter being a failure of the degradation of TNK2 by an E3 ubiquitin ligase, a neuronal precursor expressed by cells and regulated by development (NEDD4).
Interestingly, systemic RNA interference protein-3 (SID-3) is the only TNK2 ortholog in the nematode Caenorhabditis elegans, where it is an established effector of epigenetic gene silencing mediated by the dsRNA transporter, SID-1. We hypothesized that TNK2/SID-3 represents an integrated dopaminergic and epigenetic signaling node essential for neuronal homeostasis.
The use of a TNK2 inhibitor (AIM-100) or NEDD4 activator (N-aryl benzimidazole 2 (NAB2)) in bioassays for dopamine or dsRNA uptake in dopaminergic neurons of the worm revealed that sid-3 mutants displayed robust neuroprotection against 6-hydroxydopamine (6-OHDA) exposures, as did wild-type animals treated with AIM-100 or NAB2.
Moreover, activation of NEDD4 by NAB2 in primary rat neurons was correlated with reduced levels of TNK2 and attenuation of 6-OHDA neurotoxicity. CRISPR-modified nematodes engineered to endogenously express SID-3-like variants TNK2 PD-associated SNPs showed increased susceptibility to dopaminergic neurodegeneration and circumvented RNAi resistance characteristic of SID-3 dysfunction.
This research illustrates a molecular etiology of PD in which dopamine and epigenetic signaling are coordinatedly regulated to confer susceptibility or resilience to neurodegeneration.