Movement and Memory: TDP-43 Pathology in ALS-FTD

Abstract

Characterized by the progressive neurodegeneration of the motor system, amyotrophic lateral sclerosis (ALS) presents no features starkly reminiscent of dementia. However, significant clinical overlap between ALS and frontotemporal dementia (FTD), a type of non-Alzheimer’s dementia, has been identified in research, leading to a recognized spectrum of disease along which both diseases fall. This spectrum is typically unified by a common pattern of TAR DNA binding protein (TDP-43) proteinopathy or fused in sarcoma (FUS), meaning these proteins are commonly found misfolded as aggregates in diseased cells. The specific diagnosis of overlapping ALS and FTD, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD), presents a particularly intriguing, though under-investigated, area of research on a pathology that is expressed both behaviorally and physically.

Structure of TDP-43 protein

Structure of TDP-43 protein

In concert with the growing literature on the pathogenesis and progression of ALS-FTSD, my research involves generating a math-based, research-driven model of ALS-FTSD at the molecular level. The model(s) will focus on pathways of autophagy, neuroinflammation, and nuclear localization of TDP-43, while investigating the role of various mutations and treatments in the models using a biochemical simulation software. My results aim to aid the understanding of the clinical and pathological overlap found in ALS-FTSD and to test various trigger points and possible treatments using computational simulations.

 

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