Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9388660 | PMC |
| http://dx.doi.org/10.1038/s41531-022-00369-w | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Interactions of VMAT2 with CDCrel-1 and Parkin in Methamphetamine Neurotoxicity.
Int J Mol Sci
December 2024
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA.
In recent years, methamphetamine (METH) misuse in the US has been rapidly increasing, and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including the dysfunction of the neuroprotective protein parkin.
View Article and Find Full Text PDFDopamine transporter endocytic trafficking: Neuronal mechanisms and potential impact on DA-dependent behaviors.
J Neurochem
January 2025
Department of Neurobiology, UMASS Chan Medical School, Worcester, Massachusetts, USA.
The dopamine (DA) transporter (DAT) is a major determinant of DAergic neurotransmission, and is a primary target for addictive and therapeutic psychostimulants. Evidence accumulated over decades in cell lines and in vitro preparations revealed that DAT function is acutely regulated by membrane trafficking. Many of these findings have recently been validated in vivo and in situ, and several behavioral and physiological findings raise the possibility that regulated DAT trafficking may impact DA signaling and DA-dependent behaviors.
View Article and Find Full Text PDFThe role of Sod-2 in different types of neuronal damage and behavioral changes induced by polystyrene nanoplastics in Caenorhabditis elegans.
Ecotoxicol Environ Saf
December 2024
Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, Fujian Province 350122, China; The Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian Province 350122, China; Fujian Provincial Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China. Electronic address:
Article Synopsis
- Polystyrene nanoplastics (PS-NPs) are harmful substances that accumulate in organisms and cause neurotoxicity, although the specific mechanisms behind this toxicity are not well understood.
- In a study using nematodes, researchers found that PS-NPs lead to behavioral damage and harm to specific types of neurons, with significant reductions in neurotransmitter levels observed.
- The study identified that PS-NPs increase reactive oxygen species (ROS) production and decrease the Sod-2 protein, and showed that using the mitochondrial ROS scavenger Mitoquinone can help reduce these toxic effects.
Transcutaneous auricular vagus nerve stimulation in anesthetized mice induces antidepressant effects by activating dopaminergic neurons in the ventral tegmental area.
Mol Brain
November 2024
Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.
Article Synopsis
- Depression is a common disorder linked to imbalances in neurotransmitters like dopamine (DA), making DA restoration a key treatment focus.
- Both medication and non-invasive techniques, such as transcutaneous auricular vagus nerve stimulation (taVNS), have shown potential in alleviating depressive symptoms, though taVNS's exact mechanism is still under investigation.
- Experiments on mice revealed that taVNS reduces depressive-like behaviors by enhancing activity in the ventral tegmental area (VTA) and that inhibiting DA neurons in the VTA negated its effects, highlighting its role in depression treatment.
Article Synopsis
- - Mitochondrial dysfunction and oxidative stress are significant factors in age-related neurodegenerative diseases, and PKCδ isoform in dopaminergic neurons is critical for cell death during these stress events through caspase-3 activation.
- - The study revealed that upon mitochondrial dysfunction, PKCδ gets activated and moves to the nucleus, where it interacts with Lamin B1, causing nuclear damage and contributing to neuronal cell death.
- - Experiments showed that blocking PKCδ activation or modifying Lamin B1 can prevent nuclear damage, confirming PKCδ's role as a major player in neurodegenerative processes linked to mitochondrial stress.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!