Biology subjects

Galdieri, J.

Publications and source records attributed to Galdieri, J..

3 recordsLinked to original sources

bioRxiv2025

A genetically engineered vertebrate animal model of NAA15-related heart disease uncovers myocardial growth, contractility, and mitochondrial defects

Delineating the genetic and environmental instigators of congenital heart disease (CHD), affecting up to 1% of newborns, will improve preventative, diagnostic, and therapeutic efforts to mitigate disease outcomes. Although mutations in NAA15, which encodes the auxiliary subunit of N-alpha-acetyltransferase A (NatA), are associated with CHD in humans, vertebrate animal models of NAA15-related heart disease have yet to be described. Therefore, we isolated zebrafish strains carrying null mutations in paralogs naa15a and naa15b, which we co-localized to the early larval myocardium. Double knockout (DKO) naa15-deficient larvae exhibited diminutive, lowly contractile, and bradycardic ventricles composed of fewer and smaller cardiomyocytes (CMs) incapable of proliferation. On a subcellular level, mutant CMs exhibited moderately disorganized myofibrils. CM-specific re-expression of naa15a partially rescued the contractility and growth deficits, revealing an indispensable myocardial function. Ubiquitous mis-expression of human NAA15 achieved complete rescue, enabling functional testing of human NAA15 variants. Animals with a reduced dosage (RD) of naa15 survived to adulthood and shared phenotypes with DKO larvae, including smaller ventricular chambers and CMs, which exhibited mosaic myofibril disarray. Deep quantitative proteomic profiling of WT and naa15RD adult hearts revealed differential expression of multiple protein classes, including several subunits of mitochondrial respiratory complex I, a component of the electron transport chain. Accordingly, we documented reduced mitochondrial content and function in the myocardium of naa15-deficient larvae. Taken together, our data reveal myocardial functional and structural abnormalities associated with mitochondrial dysfunction in a vertebrate animal model of NAA15-related heart disease.

developmental biology↗

bioRxiv2024

The Role of Cilia in the Development, Survival, and Regeneration of Hair Cells

Mutations impacting cilia genes lead to a class of human diseases known as ciliopathies. This is due to the role of cilia in the development, survival, and regeneration of many cell types. We investigated the extent to which disrupting cilia impacted these processes in hair cells. We found that mutations in two intraflagellar transport (IFT) genes, ift88 and dync2h1, which lead to the loss of kinocilia, caused increased hair cell apoptosis in the zebrafish lateral line. IFT gene mutants also have a decreased mitochondrial membrane potential, and blocking the mitochondrial uniporter causes a loss of hair cells in wild-type zebrafish but not mutants, suggesting mitochondria dysfunction may contribute to the apoptosis seen in these mutants. These mutants also showed decreased proliferation during hair cell regeneration, but did not show consistent changes in support cell number or proliferation during hair cell development. These results show that disruption of the cilia through either mutations in anterograde or retrograde IFT genes appear to impact hair cell survival but not necessarily development in the lateral line.

neuroscience↗

bioRxiv2022

The role of calcium, Akt and ERK signaling in cadmium-induced hair cell death

Exposure to heavy metals has been shown to cause damage to a variety of different tissues and cell types including hair cells, the sensory cells of our inner ears responsible for hearing and balance. Elevated levels of one such metal, cadmium, have been associated with hearing loss and shown to cause hair cell death in multiple experimental models. While the mechanisms of cadmium-induced cell death have been extensively studied in other cell types they remain relatively unknown in hair cells. We have found that calcium signaling, which is known to play a role in cadmium-induced cell death in other cell types through calmodulin and CaMKII activation as well as IP3 receptor and mitochondrial calcium uniporter mediated calcium flow, does not appear to play a significant role in cadmium-induced hair cell death. While calmodulin inhibition can partially protect hair cells this may be due to impacts on mechanotransduction activity. Removal of extracellular calcium, and inhibiting CaMKII, the IP3 receptor and the mitochondrial calcium uniporter all failed to protect against cadmium-induced hair cell death. We also found cadmium treatment increased pAkt levels in hair cells and pERK levels in supporting cells. This activation may be protective as inhibiting these pathways enhances cadmium-induced hair cell death rather than protecting cells. Thus cadmium-induced hair cell death appears distinct from cadmium-induced cell death in other cell types where calcium, Akt and ERK signaling all promote cell death.

neuroscience↗