Unraveling the Pathology of Parkinson’s Disease
A new study identifies a microRNA implicated in the progression of Parkinson’s disease with the potential for therapeutic intervention
July 14, 2022
Parkinson’s disease (PD) is the second most prevalent aging-related neurodegenerative disorder, affecting around 10 million people worldwide. While the pathogenesis of PD is not fully understood, patients suffer a gradual and progressive loss of dopaminergic (DA) neurons in one specific area of the brain, the substantia nigra (SN), which results in a gradual loss of motor control often manifesting as a tremor or shaking in one or more limbs, and progressing over time to include slowed movement, impaired posture and balance, speech changes, difficulty with delicate tasks such as writing and eventually loss of automatic movements such as blinking or smiling.
The current medical treatment for PD focuses mainly on increasing dopamine levels in the brain, either by increasing the base level of dopamine via therapeutic dopamine pre-cursors that are converted to dopamine in the brain, using agonists that mimic the effect of dopamine, or inhibitors that prevent dopamine breakdown. All serve to increase dopamine levels and address some of the symptoms of reduced motor control in PD patients. Given the prevalence of PD, there is a clear need for a treatment that addresses the root cause of the disease, slowing or halting its progress rather than alleviating the symptoms.
MicroRNAs may represent a new and important class of therapeutic targets
While the root cause of PD is unknown, studies have implicated perturbations in gene regulation, mitochondrial function, and neuronal activity. More recently several studies have demonstrated aberrations in transcriptional and post-transcriptional gene regulation in both PD mouse models and in the post-mortem examination of brain samples from human PD patients including changes in microRNAs which operate to regulate the transcriptome and are understood to play a key role in nervous system biology. These microRNAs are responsible for the downregulation of messenger RNA (mRNA) through complementary binding and play an important role in the regulation of biological pathways. The potential of microRNAs as therapeutic targets is being investigated for a number of different disease states.
The identification of a microRNA with a key role in Parkinson’s Disease
A recent study by researchers at the University of Iowa, Department of Internal Medicine has implicated the microRNA miR-181a as a potential therapeutic candidate for the treatment of PD. miR-181a has been shown to play an important role in the regulation of genes involved in neuronal growth, neurite extension, mitochondrial biogenesis, and neuronal cell survival. The authors performed viral-mediated gain and loss of function studies in a mouse model of PD, and successfully demonstrated that increased levels of miR-181a promoted DA neuronal degradation, and that suppressing its activity protected animals against PD-related neurotoxicity.
Viral mediated gene regulation in an animal model of PD
The in vivo manipulation of miR-181a levels in a mouse model of PD required for gain and loss of function studies required the creation of plasmids and adenoviral vectors (AVV) to overexpress or inhibit miR-181a levels in mice. AAV vectors were prepared containing promotor or inhibitor coding sequence and packaged into viral capsids using standard triple transfection methods. Once packaged the authors selected AcrodiscÒ syringe with Mustang Ò Q membranes for the critical filtration step prior to direct intra-parenchymal injection of viral vectors into the SN region of the mouse brain. Mustang Q is a strong ion exchange membrane that effectively binds any remaining free (unpackaged) plasmid DNA and any other negatively charged particulate matter that might be present in the suspension, resulting in a pure suspension of plasmid DNA packaged within viral capsid vectors and ready for injection.
The identification of the role of miR-181a in the progression of PD represents an important step forward in the understanding of the mechanism of PD and presents a potential new therapeutic target for investigation. The development of a treatment for PD that addresses the underlying biology of the disease rather than simply regulating its symptoms remains a key goal for researchers, and the identification of miR-181a moves us an important step closer.
You can learn more about the Acrodisc syringe and Mustang Q membrane here.
1. Mayo Clinic. Diseases and conditions: Parkinson’s disease. [online] available at: https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/symptoms-causes/syc-20376055 [Accessed 22 March 2022]
2. Stein CS, et al. Modulation of miR-181 influences dopaminergic neuronal degeneration in a mouse model of Parkinson’s disease, Molecular Therapy: Nucleic Acid (2022), doi: https://doi.org/10.1016/j.omtn.2022.02.007