Biology subjects

Sayles, N. M.

Publications and source records attributed to Sayles, N. M..

4 recordsLinked to original sources

bioRxiv2024

Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.

CHCHD10 is mutated in rare cases of FTD and ALS and aggregates in mouse models of disease. Here we show that the disordered N-terminal domain of CHCHD10 forms amyloid fibrils and report their cryoEM structure. Disease-associated mutations cannot be accommodated by the WT fibril structure, while sequence differences between CHCHD10 and CHCHD2 are tolerated, explaining the co-aggregation of the two proteins and linking CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration.

biophysics↗

bioRxiv2023

High fat diet ameliorates the mitochondrial cardiomyopathy of CHCHD10 mutant mice

Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress.

molecular biology↗

bioRxiv2023

Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency

Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, the FA heart maintains adequate function until disease end stage, suggesting that it can initially adapt to the loss of frataxin (FXN). Conditional knockout mouse models with no Fxn expression show transcriptional and metabolic profiles of cardiomyopathy and mitochondrial integrated stress response (ISRmt). However, ISRmt has not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models of partial FXN loss, YG8-800, KIKO-700, and FxnG127V. Few metabolites were significantly changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has extremely low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy. Summary statementThe mitochondrial integrated stress response in the heart of a Friedreich Ataxia mouse model is surprisingly mild, despite a severe decrease in frataxin levels below 1% of normal.

molecular biology↗

bioRxiv2019

Single chromosome gains can function as metastasis suppressors and metastasis promoters

Most human tumors display chromosome-scale copy number alterations, and high levels of aneuploidy are frequently associated with advanced disease and poor patient prognosis. To examine the relationship between aneuploidy and cancer progression, we generated and analyzed a series of congenic human cell lines that harbor single extra chromosomes. We find that different aneuploidies can have distinct effects on invasive behavior: across 13 different cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, chromosomal instability, which can lead to the development of aneuploidy, uniformly suppressed cellular invasion. By analyzing genomic copy number and survival data from 10,133 cancer patients, we demonstrate that specific aneuploidies are associated with distinct clinical outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis. Thus, aneuploidy is not a uniform driver of malignancy, and different chromosome copy number changes can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, underscoring how genomic plasticity can engender phenotypic plasticity and lead to the acquisition of enhanced metastatic properties.

cancer biology↗