Moy ortiz biography of martin luther king

Background: The mechanism by which polymorphisms in the anti-aging protein klotho lead to increased disease risk is unknown.

Results:In vitro, klotho-VS decreases homodimerization and increases heterodimerization with and activation of FGFR1c.

Conclusion: Altered dimerization explains klotho-VS association with increased disease risk.

Significance: Understanding how the VS variant leads to changes in klotho function will elucidate the role klotho plays in disease and lifespan.

Keywords: Aging, Cell Signaling, Fibroblast Growth Factor Receptor (FGFR), Genetic Polymorphism, Protein Complexes, Shedding, Dimerizaion

Abstract

Klotho (KL) is an age-regulating protein named after the Greek goddess who spins the thread of life. Mice deficient in KL are normal throughout development, but rapidly degenerate and display a variety of aging-associated abnormalities that eventually lead to decreased life expectancy. While multiple genetic association studies have identified KL polymorphisms linked with changes in disease risk, there is a paucity of concrete mechanistic data to explain how these amino acid substitutions alter KL protein function. The KLVS polymorphism is suggested to lead to changes in protein trafficking although the mechanism is unclear. Our studies have sought to further investigate the functional differences in the KLVS variant that result in increased risk of many age-related diseases. Our findings suggest that the F352V and C370S substitutions lead to alterations in processing as seen by differences in shedding and half-life. Their co-expression in KLVS results in a phenotype resembling wild-type, but despite this intragenic complementation there are still changes in homodimerization and interactions with FGFR1c. Taken together, these studies suggest that KLVS leads to altered homodimerization that indirectly leads to changes in processing and FGFR1c interactions. These findings help elucidate the functional differences that result from

Abstract

Cytoplasmic TDP-43 mislocalization and aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is an RNA-binding protein (RBP) with a prion-like domain (PrLD) that promotes TDP-43 misfolding. PrLDs possess compositional similarity to canonical prion domains of various yeast proteins, including Sup35. Strikingly, disease-causing TDP-43 mutations reside almost exclusively in the PrLD and can enhance TDP-43 misfolding and toxicity. Another ∼70 human RBPs harbor PrLDs, including FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2, which have surfaced in the etiology of neurodegenerative diseases. Importantly, PrLDs enable RBP function and mediate phase transitions that partition functional ribonucleoprotein compartments. This PrLD activity, however, renders RBPs prone to populating deleterious oligomers or self-templating fibrils that might spread disease, and disease-linked PrLD mutations can exacerbate this risk. Several strategies have emerged to counter TDP-43 proteinopathies, including engineering enhanced protein disaggregases based on Hsp104.

TDP-43 misfolds and aggregates in amyotrophic lateral sclerosis and may contribute to other neurodegenerative conditions. Therapeutic strategies that reverse TDP-43 misfolding (e.g., engineered protein disaggregases) are under development.

One of the greatest biomedical challenges of our era lies in the daunting reality that there continues to be no effective therapies for several ineluctably fatal and increasingly common neurodegenerative disorders connected with protein misfolding, soluble toxic oligomers, and aberrant protein aggregation (Cushman et al. 2010; Eisenberg and Jucker 2012; Prusiner 2013). One of these debilitating neurodegenerative disorders, amyotrophic lateral sclerosis (ALS), is the most common adult motor neuron disease, afflicting ∼2 individuals per 100,000, with typi