Moderator of 2 Sessions
Symposium Working Summary: This day-long, CME credit-eligible workshop will provide participants with an understanding of the common and distinct features of neurological and ocular degenerative disease. This session will address how to use analytic and computational tools to wrangle large datasets, spot patterns that may not be inherently obvious, and sort through thousands, if not millions, of health records to find and recruit eligible participants with health equity and population representation in mind. This fifth pre-conference workshop will begin with a look at using big data to discover how disease begins and advances (Section 1. Mechanistic Insight from Multi-Omics and Imaging), then progress to probing increased or decreased risks in individuals or populations, as well as developing precision diagnoses (Section 2. Big Data in Biomarker Discovery and Diagnoses), and end with a more wholistic point of view of clinical studies (Section 3. Big Data in Clinical Studies). Some questions that will be addressed: Questions to consider: • What is ‘big data’? • Do I have to be an expert at ‘big data’ to use it in my research? • What are some open access (or easily accessible) ‘big data’ resources for researchers- especially with regards to neurological and ocular degenerative diseases? • How does the multi-etiology nature of dementia and other neurodegenerative diseases complicate biomarker development and diagnoses? • How can I use ‘big data’ to design clinical studies that represent the general population and ensure health equity should a treatment make it to the market? • How can I use ‘big data’ to determine differences between sexes, racial/ethnic groups, and potential environmental or socio-economic differences between populations? • Are there common origins and/or elements across brain and eye neurodegenerative diseases that could give us a clue to future risk reductions, better and earlier detection of disease, and disease-modifying treatments?
Presenter of 2 Presentations
TMEM106B CODING VARIANT IS PROTECTIVE AND DELETION DETRIMENTAL IN A MOUSE MODEL OF TAUOPATHY
Abstract
Aims
TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP models to tauopathy.
Methods
We generated two mouse models to explore the impact of TMEM106B within the context of tau pathology. One model featured a constitutive null mutation, while the other incorporated a homozygous T186S knock-in mutation (equivalent to the human T185S variant). These lines were bred with a transgenic P301S tau model (PS19) to yield eight genotypes for study: WT, KO, Tau, and KO:Tau; plus WT, Tau, KI, and KI:Tau. Animals underwent a battery of cognitive assays at 6 or 9 months of age before brain tissue was harvested to examine the effect of TMEM manipulation on neuropathology and transcription.
Results
We found that TMEM106B deletion accelerated cognitive decline, hindlimb paralysis, tau pathology, and neurodegeneration. TMEM106B deletion also increased transcriptional correlation with human AD and the functional pathways enriched in KO:tau mice also aligned with those of AD. In contrast, the coding variant protected against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology.
Conclusions
Our findings reveal that TMEM106B is a critical safeguard against tau aggregation, and that loss of this protein has a profound effect on the sequelae of tauopathy. Our study further demonstrates that the coding variant is biologically active and contributes to neuroprotection downstream of tau pathology to preserve cognitive function.