Multiple Sclerosis as a Noncanonical Tauopathy
Abstract
Tau is a protein that helps stabilizing the structure of neuronal cells in the nervous system. However, tau can also form toxic protein aggregates that are typically found in the brain of patients suffering from Alzheimer s disease (AD) and related neurodegenerative disorders. These aggregates have the unique property to replicate themselves and trigger the formation of new tau aggregates in the neighboring neuronal cells. The spread of tau aggregates in the brain can amplify over time the initial toxic insult and is believed to account for the progressive nature of AD and all the chronic neurological disorders characterized by tau aggregation. The present research plan builds on this knowledge and proposes to explore whether tau aggregation also takes place in multiple sclerosis (MS), addressing the FY21 MSRP Focus Area on Factors contributing to MS etiology, prodrome, onset, and disease course. In particular, we hypothesize that the spreading of tau aggregates in the MS brain could be directly connected with the progressive forms of the disease, which are characterized by the irreversible accumulation of neurological disability. In agreement with this model, we have shown that tau aggregates can indeed be isolated from the brain of progressive MS patients. To test our hypothesis, we will measure the capacity of MS tau aggregates to spread in the brain of experimental animal models. Specifically, tau aggregates will be purified from a collection of MS and control brain specimens that are available at UCSF and injected in the brain of laboratory mice. At specific time points after the injection, their brains will be analyzed for the accumulation of tau aggregates and for pathological signs of neurodegeneration. In the short term, the present project has the potential to unveil a novel molecular mechanism underlying the transition from the initial inflammatory phase to the progressive stages of the disease. In the long term, this proposal may pave the way to innovative therapeutic solutions targeting tau aggregation, in order to delay or even block the worsening of brain damage for those patients already in the progressive phase. In addition, early intervention could also be beneficial for MS patients still in the relapsing-remitting phase, potentially preventing disease conversion. Importantly, the synergy with existing programs focused on developing tau-targeting therapies for AD patients could significantly reduce the time frame to bring this research to the clinic. In summary, this project will increase our current knowledge on the pathogenic mechanisms driving MS progression, with strong implication for its therapeutic management.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210517
Entities
People
- Alessandro Didonna
Organizations
- East Carolina University
- United States Army