Biochemical Modeling: Choosing the Path(way)

Happy Friday! The first week and a half of summer research have been chock-full of information as I’m reading previous studies in the literature and trying to piece together errant pathways from exciting gene databases and benchwork results. As I grow increasingly immersed in the shifting landscape of molecular and biochemical research, I must constantly remind myself to see the big picture: how do amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) develop and progress in the body? As well exhibited in the graphic below, there seem to be a thousand and one possible pathways that light the fire and initiate the disease (aka the pathogenesis). And while it is certainly possible (and pretty likely) that several different problems lead to the same issue(s), I’m searching for some underlying themes that connect these cases of life-altering disease.

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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.

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A Testable Computational Model of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive neurodegeneration of the motor system, clinically described as the degeneration of both upper motor neurons and lower motor neurons. ALS involves the impairment of muscle nourishment, resulting in a progressive loss of voluntary muscle function, and eventually the inability to speak, eat, or breathe.  Research on this fatal disease concentrates around several intertwined areas of concern, including disease diagnosis and progression, therapies for primary and secondary consequences of ALS phenotypes, and identification of its cause (Kiernan et al., 2011, p. 942). Currently, the field has identified several genetic and mechanistic factors implicated in ALS development; cell death in ALS patients has been linked to irregularities in glutamate, a vital neurotransmitter, in calcium function, and to several genetic mutations (Corcia et al., 2017, p. 255). Because neither the cause nor cure of ALS has yet been uncovered, persistent and synergistic research must continue in order to advance the understanding of this disease and contribute to methods of prevention, alleviation, and treatment. In concert with the growing literature on the pathogenesis and progression of ALS, I plan to generate a math-based, research-driven model of the disease at the molecular level to aid the understanding of the disease state of the cell and to test various trigger points and possible treatments.

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