Prion-like Neurodegeneration

Increasing evidence for a “prion-like” spread for tau protein inclusions following Traumatic Brain Injury (TBI) is being increasingly reported in the literature. This is critical since the effects from even a mild TBI can last for a long time impacting quality of life. Consequences such as Alzheimer’s disease (AD) or even more commonly, Chronic Traumatic Encephalopathy (CTE), develop after repeated mild TBI or concussion. Understanding what may be occurring at the cellular level may allow for paradigm shifts in drug target identity.  Using controlled cortical impact (CCI), several research groups found neuronal inclusions and widespread cognitive deficits in injured animals.

pHLOGISTIX scientists have used the CCI model to assess the benefits of treating mild TBI in mice with fragments of recombinant thrombomodulin (rTM) to improve neurobehavioral deficits and reduce abnormal protein aggregation into neuronal inclusions.  Over the last two years prion-like, abnormal protein aggregation has been documented not only for tau but for also for α-synuclein (α-syn), dominant protein in Lewy bodies (LBs) in Parkinson’s disease (PD), as well as TDP-43 in amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease) inclusions.  Several groups have utilized rodents, either rats or mice, with mutations in various genes or even native animals and showed evidence for the prion-like spread.  Such reports underscore the company’s efforts to define new drug targets while emphasizing that rTM, especially the C-type lectin D1 domain of, has significant benefit in reducing neuroinflammation and decreasing protein aggregation.

Dr. Stanley Prusiner, Nobel Prize winner for Physiology or Medicine in 1997 from the University of California San Francisco (UCSF) for the initial discovery and understanding of prion proteins in scrapie, mad cow disease and Jakob-Creutzfeldt diseases in the 1980s, is developing an approach to formation of “tau prions” in transgenic mice following TBI. This model is critical since for new drug discovery efforts since conversion of native tau to prion tau with progression to CTE is more uniform than in other tau diseases (“tauopathies”) and occurs much more rapidly. Furthermore, in a study funded by the Dana Foundation , UCSF scientists are using genetically-engineered bioluminescent molecular imaging of tau to monitor serial changes in TBI-injured single animals over time in order to facilitate understanding of disease processes correlated with neurobehavior.  Furthermore, Drs. Virginia Lee, John Trojanowski and their colleagues at the University of Pennsylvania Center for Neurodegenerative Disease Research have shown that preformed fibrils (PFFs) of α-syn can form tau protein inclusions in neurons in mice injected with these PFFs and that different “strains” of PFFs will or will not induce tau “prions.”.

Although in most cases the classic prion diseases are infectious, whereas at present prion-like proteins in AD, PD, ALS or CTE appear only to seed aggregates, nonetheless in all cases the aggregated proteins gain a toxic function (“gain of function”) and/or lose normal function (“loss of function”). So, the prion paradigm, as a unifying pathogenic principle, may allow for new therapeutic directions in this large class of untreatable diseases.

Regardless whether infectious or seed-capable, these seminal observations inform pHLOGISTIX drug development, as well as our diagnostic endeavors and will guide future strategies.