• CircRNAs and Neurodegenerative Disease (PD): The Kadener Lab has leveraged its RNA expertise to explore how RNA profiles change in disorders such as Parkinson’s. In a collaborative study (EMBO Molecular Medicine2020), they created a comprehensive Parkinson’s Disease circRNA resource by sequencing brains of PD patients versus healthy controls. An important finding was that in the healthy aging brain (specifically the substantia nigra region), circRNA levels normally increase with age, but in Parkinson’s patients this age-related accumulation is disrupted. PD patients had an overall reduction in circRNA abundance in the substantia nigra compared to age-matched controls, suggesting circRNA biogenesis or stability is altered in disease. Intriguingly, in other brain regions of PD patients, circRNA levels were increased, indicating region-specific differences.

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• Specific CircRNA as a PD Biomarker: From that study, one circRNA in particular, circSLC8A1, stood out. The lab found circSLC8A1 is significantly upregulated in the substantia nigra of individuals with Parkinson’s disease. This circRNA carries multiple binding sites for miR-128, a microRNA involved in neuronal oxidative stress responses, and was shown to bind strongly to the Argonaute protein (which suggests it sequesters miR-128). Consistently, the mRNA targets of miR-128 were found to be increased in PD brains, implying that when circSLC8A1 levels rise, it might sponge miR-128 and thereby dysregulate oxidative stress pathways. The lab also demonstrated in cell experiments that circSLC8A1 levels go up under oxidative stress (e.g. when cells are exposed to a toxin) and go down with an antioxidant treatment. Together, these results link circSLC8A1 to the oxidative stress aspect of Parkinson’s and suggest it could be a marker or even contributor to the disease process. This kind of finding is valuable for understanding neurodegeneration and potentially identifying new therapeutic targets or biomarkers.

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• LncRNAs and Neuroprotection: Apart from circRNAs, the lab has dabbled in long noncoding RNAs in neurodegeneration. For instance, they reported changes in lncRNAs like NEAT1 and LINC-PINT in Parkinson’s disease patient brains (Simchovitz et al., Aging Cell 2020; Simchovitz et al., FASEB J 2019). One interesting result was that NEAT1 is overexpressed in PD and might have neuroprotective effects. While these might be side notes, mentioning them shows the lab’s broad interest in RNA-based mechanisms in neurodegeneration.