NEMO, a protein that is primarily associated with signaling processes in the immune system, prevents the deposition of protein aggregates that occur in Parkinson’s disease. For this purpose, it binds to certain protein chains that serve as markers for cellular waste removal, thus promoting the degradation of the harmful aggregates. A research team headed by Professor Konstanze Winklhofer from Ruhr University Bochum, Germany, has shed light on how this mechanism works. The team published their findings in the journal Nature Communications from December 19, 2023. In follow-up studies, the team is investigating ways to harness the findings for therapeutic strategies.

Looking for targeted therapeutic approaches

Neurodegenerative diseases, such as Parkinson’s or Alzheimer’s disease, are associated with the deposition of protein aggregates in the brain. These aggregates accumulate when the cellular waste removal system is defective or overloaded. In Parkinson’s disease, aggregates consisting primarily of the protein ⍺-synuclein are found in certain regions of the brain. “The fact that such aggregates occur, which are referred to as Lewy bodies, is a key feature of Parkinson’s disease,” explains Konstanze Winklhofer.

Researchers from various disciplines around the world are therefore aiming to decipher these processes at a cellular and molecular level, in order to develop targeted therapeutic approaches.

Labeled proteins are degraded

In collaboration with an interdisciplinary team, the Bochum-based research group has succeeded in gaining a better understanding of the mechanism of ⍺-synuclein degradation: Cellular proteins that are destined for degradation are labeled so that the cellular waste disposal system can identify these proteins. This label consists of a chain of ubiquitin molecules.

The protective effect of NEMO protein

In previous studies, the research group has shown that a specific form of ubiquitin chains, so-called linear ubiquitin chains, accumulates on protein aggregates in neuronal cells and reduce the toxicity of the protein aggregates. The researchers have now finally identified the mechanism of this protective effect. They found that the protein NEMO docks to linear ubiquitin chains on the protein aggregates and promotes the degradation of ⍺-synuclein.

“What’s interesting is that the protective effect of NEMO can be blocked by inhibiting autophagy,” explains Winklhofer.

The research group of Konstanze Winklhofer discovered that NEMO interacts with a protein of the autophagy machinery. By forming a complex consisting of linear ubiquitin chains, of NEMO and the said protein called p62 on the ⍺-synuclein aggregates, p62 can be arranged in the form of condensates – which is essential for the efficient recruitment of the autophagy machinery to protein aggregates.

Mutation in the NEMO gene results in early and severe disease

“A milestone during this research was a conversation with neurologists from the University of San Francisco, who had contacted me about an interesting case,” says Konstanze Winklhofer. Her US colleagues were treating a patient with progressive Parkinson’s disease who had fallen ill in her early 40s. They therefore ran a genetic test, which revealed that this patient had a rare mutation in the NEMO gene. “Our biochemical and cell biological characterization of the NEMO variant showed that it’s unable to bind to linear ubiquitin chains and therefore can’t dock to protein aggregates.” The loss of function of NEMO impairs the formation of p62 condensates on ⍺-synuclein aggregates and disrupts their degradation.

In fact, a pronounced deposition of ⍺-synuclein aggregates was found in the brain of the patient with the NEMO mutation.

The research team is conducting follow-up studies to explore the potential of NEMO and linear ubiquitin chains for new therapeutic strategies.(VP/Newswise)