Identification and characterisation of IFNAR1C291* , a rare mutation in familial Parkinsonian disorders
- Abstract number
- 129
- Event
- European Microscopy Congress 2020
- DOI
- 10.22443/rms.emc2020.129
- Corresponding Email
- [email protected]
- Session
- LSA.7 - Pathology, immunocytochemistry and biomolecular labelling
- Authors
- Mr Lluís Riera Ponsati (1), Dr Emilie Tresse-Gommeaux (1), Dr Shohreh Issazadeh-Navikas (1), Dr Florian Krismer (2), Dr Klaus Seppi (2), Dr Oliver Kretz (4), Dr Alexander Zimprich (3)
- Affiliations
-
1. Biotech Research and Innovation Centre
2. Medical University Innsbruck
3. Medizinische Universität Wien
4. University Medical Center Hamburg-Eppendorf
- Keywords
Parkinson's Disease, Neurodegeneration, Neuroimmunology, Type I Interferons
- Abstract text
Parkinsonian disorders, including Parkinson’s disease (PD), are the second most common class of neurodegenerative disorders. PD produces a progressive decline in motor and cognitive functions with no cure. Despite numerous efforts, PD is largely sporadic with unknown aetiology (1). Nevertheless, studies of rare familial forms have identified genetic mutations– shedding light on the underlying pathophysiology (2,3,4). Here, we report the identification of a novel, nonsense, disease-linked mutation of the interferon a/b receptor 1 (IFNAR1) gene, p.(C291*), in a family affected by parkinsonian disorders. We found that the p.(C291*) mutation confers loss-of-function and defective neuronal IFNb-IFNAR-signaling, as it encodes for a truncated version of the receptor, with partial deletion of the extracellular domains, transmembrane domain and cytoplasmic tail. IFNAR1C291* expression in primary neurons and had a dominant-negative effect, causing defective neuronal morphology and the pathological hallmarks of PD: accumulation of senesced mitochondria, increased oxidative stress, lowered ATP production, and intracellular inclusions containing phosphorylated a-synuclein, Tau and ubiquitin, as assessed through light and electron microscopy. Furthermore, in vivo IFNAR1C291* expression in neurons led to motor and cognitive defects, accompanied by dopamiergic cell loss. Our data reveal a new link between innate immunity and Parkinsonian disorders, highlighting new pathogenic mechanisms involved in the aetiology of the disease.
- References
Kalia, L.V., and Lang, A.E. (2015). Parkinson's disease. Lancet 386, 896-912.
Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R.J., Calne, D.B., et al. (2004). Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607.
Polymeropoulos, M.H., Lavedan, C., Leroy, E., Ide, S.E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276, 2045-2047.
Deng, H.X., Shi, Y., Yang, Y., Ahmeti, K.B., Miller, N., Huang, C., Cheng, L., Zhai, H., Deng, S., Nuytemans, K., et al. (2016). Identification of TMEM230 mutations in familial Parkinson's disease. Nat Genet 48, 733-739.