Additionally, this promising approach could also be applied to other brain disorders caused by protein aggregation inside cells, such as motor neuron disease, Huntington’s disease, and Parkinson’s disease.
The study demonstrates how the exploitation of the TRIM21 protein can bring 2 major advantages to therapies:
- specifically targeting disease-related tau aggregates, leaving healthy tau proteins intact;
- the potency or ability to eliminate already established tau aggregates – not just the formation of new aggregates.
2 major proteins are involved in these neurodegenerative diseases: these proteins, tau and amyloid, fold poorly and accumulate in aggregates in the brains of affected people.
- Regarding amyloid, its aggregates which form in the spaces between brain cells can today be targeted by new antibody therapies, such as lecanemab;
- in contrast, tau “tangles” primarily form inside nerve cellsalthough aggregates can spread from cell to cell. These aggregates are therefore more difficult to target: antibody therapies have difficulty accessing the tau protein inside cells, at best they prevent the aggregates from spreading.
- Other techniques for targeting tau inside cells, such as antisense oligonucleotides (ASOs), have been shown to reduce tau in promising early-stage clinical trials. However, they act on all tau proteins in the brain and therefore also eliminate “healthy” tau protein – with very likely long-term side effects – which remain poorly understood. Especially since “healthy” tau protein normally helps provide structural support inside nerve cells in the brain – acting as a sort of scaffolding.
The new targeting technique tau protein tangles uses a 2010 discovery by some scientists on the same team, about the role of a unique protein called TRIM21, a key agent in the immune response to viruses. Outside the cell, the body produces antibodies that bind to invading viruses. When antibody-bound virus enters a cell, TRIM21 detects it and labels it as “waste,” passing it to the proteasome for destruction.
The idea being that TRIM21 could be used to also destroy tau aggregates associated with Alzheimer’s.
By replacing antibodies that bind to viruses with antibodies that bind to tau, TRIM21 was redirected to send the tau protein aggregates to be destroyed by the proteasome.
TRIM21 is particularly suited to this task due to a particular characteristic: a part of the protein called “RING” is activated only when 2 or more TRIM21 proteins come together. This means that it only activates and marks its target for destruction when TRIM21 proteins are bound to adjacent aggregated tau proteins.
The study therefore uses TRIM21 again to develop 2 new therapies targeting tau aggregates and confirms their effectiveness in vitro and in the mouse model of tauopathy:
- the first therapy, “RING-nanobody,” combines a tau-binding nanobody – a miniature version of an antibody – with the TRIM21 RING;
- the second therapy, “RING-Bait,” combines the TRIM21 RING with a copy of the tau protein itself. The RING-bound tau protein acts as a bait – the aggregates incorporate it and TRIM21 RING is also incorporated. Once multiple RINGs are added to the aggregate, they are activated and cause the entire aggregate to be destroyed.
In other words, these strategies are effective in eliminating tau aggregates hidden inside brain cells: here, the treated mice reverse their neurodegeneration and walk better after therapy: within a few weeks, a significant reduction in the amount of aggregated tau in the brain cells of treated animals is observed.
“We found a way to not only break down tau aggregates, but still preserve healthy tau so it can do its job.” A new strategy that goes beyond current ASO therapies currently being tested, as it could avoid any potential side effects related to eliminating normal tau.”
Other neurodegenerative diseases are caused by aggregates formed by other proteins, such as TDP43 in motor neuron disease and alpha-synuclein in Parkinson’s disease.
“It is hoped that these strategies will also enable the development of future therapies that directly target the aggregation process in these diseases.”
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