Controlling neurodegeneration by modulating the crosstalk between inflammation and proteinopathy
Description: Two hallmarks common to all neurodegenerative diseases are chronic neuroinflammation and proteinopathy, processes that actively amplify each other. Mutations in optineurin, an adaptor protein implicated in various cellular functions including inflammatory signalling and autophagy, have been found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the mechanistic role of optineurin in neurodegeneration in ALS/FTD, we have generated a mouse model in which the ubiquitin-binding region of optineurin was deleted, mimicking C-terminal truncations found in patients. Interestingly, optineurin-interacting proteins, such as Tank binding kinase 1 (TBK1), have also recently been found in ALS and FTD patients, suggesting that they participate in a shared neuroprotective pathway. Here we will follow-up two key observations from our initial characterization of the Optn470T model where we found that the lack of functional optineurin precluded optimal TBK1 activation and IFN-ß production in microglia and macrophages, leading to a disbalance in proinflammatory and anti-inflammatory factors, and that aged Optn470T mice developed pathognomonic ALS/FTD aggregates containing TDP-43 and ubiquitin in their frontal cortices. To this end, we will 1) apply novel CRISPR-generated cellular systems of optineurin deficiency to elucidate the crosstalk between protein aggregation and inflammation in vitro, and 2) manipulate the disease course in the in vivo ALS/FTD models by selected genetic and viral tools. In particular, based on our results that optineurin is a key regulator of the immunomodulatory IFN-ß pathway, a special focus will be to deliver IFN-ß intrathecally by adenovirus-associated virus 2/9 gene therapy. Overall, by addressing several outstanding questions on optineurin, a neuroprotective molecule at the crossroads of inflammation and proteinopathy, we intend to pinpoint the most likely pathway(s) for therapeutic manipulation.
Funder: Hrvatska Zaklada za Znanost
Amount: €132,700
Funding type: grant
Funder scheme: IP
Start date: 2019-03-25
End date: 2023-09-24
Investigator: Ivana Munitić
Institution: University of Rijeka, Faculty of Biotechnology and Drug Development
Funded outputs count: 10
Funder award ID: IP-2018-01-8563
OpenAlex ID: G8964355177