Self-propagating protein conformations as targets of intracellular immunity (360G-Wellcome-206248_Z_17_Z)
Recent discoveries in neurodegeneration support the cell-to-cell transmission and replication of certain ‘prion-like’ proteins in a manner highly reminiscent of viral infection. This suggests that antiviral mechanisms could potentially be used to treat neurodegenerative diseases. The novel antibody receptor TRIM21 engages immune complexes in the cytoplasm and elicits their proteasome-dependent destruction. This activity prevents infection by viruses that enter the cell with antibodies attached to them. Preliminary data show that seeds of tau, a cytoplasmic prion-like protein that aggregates in Alzheimer’s disease, can similarly be neutralized in this way. This study will combine high-content cellular seeding assays, degradation assays and two mouse models of tau pathology to investigate the mechanism of antibody protection during immunotherapy. Using antibody engineering and knockout mice lines, I will quantify the contribution of TRIM21 and classical Fc receptors to immunotherapeutic protection against neurodegeneration. I will determine how cellular machinery elicits the inactivation of prion-like proteins. This combined approach will support an understanding of intracellular inactivation of prion-like proteins and relate it to disease progression. Current understanding has not translated into disease-modifying therapeutic interventions for neurodegeneration. These studies may inform new strategies aimed at limiting spread of pathogenic protein assemblies using antibodies.
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Grant Details
Amount Awarded | 964847 |
Applicant Surname | McEwan |
Approval Committee | Sir Henry Dale Fellowship Interview Committee |
Award Date | 2017-02-22T00:00:00+00:00 |
Financial Year | 2016/17 |
Grant Programme: Title | Sir Henry Dale Fellowship |
Internal ID | 206248/Z/17/Z |
Lead Applicant | Dr William McEwan |
Partnership Name | Royal Society/Wellcome Trust Sir Henry Dale Fellowship |
Partnership Value | 964847 |
Planned Dates: End Date | 2025-09-03T00:00:00+00:00 |
Planned Dates: Start Date | 2017-09-04T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | East of England |
Sponsor(s) | Prof Giovanna Mallucci, Prof Patrick Chinnery |