Issazadeh-Navikas Group

Our team focuses on neuronal immunity, the interaction between the immune and central nervous systems—specifically, the cross-regulation between immune genes and neurons in the CNS. Ultimately, our aim is to understand the mechanisms by which these cells communicate with and govern each other. We hope to identify shared molecules that are central to the stability, integrity, and function of neurons in the CNS, which also play a central role in reprogramming pathogenic T cells that enter the CNS. These neuroimmunoregulatory genes could then be targeted therapeutically to treat and prevent neuroinflammation and neurodegenerative diseases.

IFN‐β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1:
All cells require energy provided by mitochondria for their normal function and survival. Energy demanding neurons are particularly dependent on proper mitochondrial function, to allow their fast and rapid signaling along axons extending far from the cell soma. In a recent paper¹, we report that endogenous type I interferon (IFN) signaling is essential for maintaining a healthy mitochondrial status in neurons, by allowing the separation and 2removal of damaged mitochondria via a process called mitochondrial fission. This is particularly important to also generate correctly sized mitochondria which can be transported along the axons, and therefore provide energy locally, specifically in myelinated axons. Lack of IFNb causes impaired STAT5, PGAM5 and Drp1 signaling and unsuccessful endoplasmic reticulum (ER) wrapping around the damaged mitochondria to complete fission. This leads to accumulation of huge and damaged mitochondria, which clot the axons and thereby prevents their proper energy supply and gradual degeneration. These findings have relevance for neurodegenerative diseases including Multiple sclerosis and Parkinson’s disease (IFN‐β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1. Emilie Tresse, Lluís Riera‐Ponsati, Elham Jaberi, Wei Qi Guinevere Sew, Karsten Ruscher, Shohreh Issazadeh‐Navikas. EMBO J (2021)e106868.)

MitoSV-seq: An advance in mitochondrial DNA sequencing: We have developed MitoSV-seq, a high-resolution technique that sequences all types of variations in mitochondrial DNA in single cells, including neurons, with which we identified a hotspot of mutations that is common to neurodegeneration and several cancers (Jaberi et al. EBioMedicine 2020).

Neuronal immune genes are central in preventing neurodegeneration: We have identified that several immune genes are essential for neuronal homeostasis and function. Accordingly, we determined that the lack of the immunoregulatory cytokine IFNβ or its receptor, IFNAR1, is sufficient to cause spontaneous neurodegeneration and deficits in motor coordination and cognition in mice—resembling Parkinson disease dementia and dementia with Lewy bodies (Figure) (Ejlerskov et al. Cell 2015).

Neurons tame pathogenic T cells in CNS: We have discovered that neurons are central in regulating neuroinflammation—taming pathogenic T cells and reprogramming them to become FoxP3⁺ T (Liu et al. Nature Medicine 2006) and FoxA1⁺T regulatory T cells (Liu et al. Nature Medicine 2014). The latter, FoxA1⁺ T_regs, are a novel population of regulatory T cells that we identified as being induced by IFNβ to prevent neuroinflammation in multiple sclerosis and its animal model, EAE.

Neuronal immune genes are essential for reprogramming encephalitogenic T cells: We have determined that neuronal expression of immunoregulatory genes, such as TGFβ and B7.1, is critical in the crosstalk between neurons and pathogenic T cells and for neuronal capacity to reprogram encephalitogenic T cells into FoxP3⁺ T_regs (Liu et al. Nature Medicine 2006). We have also found neuronal IFNβ and PD-L1 to be central for the generation of FoxA1⁺T_regs (Liu et al. Nature Medicine 2014, Liu et al. Nature Communications 2017).

Science4ChildrenDK- An outreach initiative in which children aged 8-11 years discover science with real-life scientists through on-site visits to schools by members of the Issazadeh-Navikas lab and trips to BRIC to design and perform basic experiments and learn about microscopy.