TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD), the leading indication for corneal transplantation in the U.S., causes loss of corneal endothelial cells (CECs) and corneal edema leading to vision loss.

Active Site Environment and Reactivity of Copper-Aβ in Membrane Mimetic SDS Micellar Environment.

Alzheimer's disease (AD) is characterized by the abnormal aggregation of amyloid β (Aβ) peptide in extracellular deposits generated upon proteolysis of Amyloid Precursor Protein (APP). While copper (Cu(II)) binds to Aβ in soluble oligomeric and aggregated forms, its interaction with membrane-bound Aβ remains elusive. Investigating these interactions is crucial for understanding AD pathogenesis.

Rapid autoxidation of ferrous heme-Aβ complexes relevant to Alzheimer's disease.

Heme bound Aβ peptides have been reported to reduce O by 2e to HO which may result in oxidative stress commonly encountered in Alzheimer's disease. In this study we report the first instance of rapid freeze quench trapping and characterizing the heme(III)-O˙ intermediate involved in the heme-Aβ induced formation of partially reduced oxygen species (PROS) in physiologically relevant aqueous medium using absorption and resonance Raman spectroscopy. The kinetics of this process indicates a key role of the Tyr10 residue, unique to human Aβ, in the generation of HO from O.

Heme-Aβ in SDS micellar environment: Active site environment and reactivity.

Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disorder that causes brain cell death. Oxidative stress derived from the accumulation of redox cofactors like heme in amyloid plaques originating from amyloid β (Aβ) peptides has been implicated in the pathogenesis of AD. In the past our group has studied the interactions and reactivities of heme with soluble oligomeric and aggregated forms of Aβ.

In situ transduction of cells in human corneal limbus using adeno-associated viruses: an ex vivo study.

This study aimed to evaluate the efficacy of in situ adeno-associated virus (AAV)-mediated gene delivery into the human corneal limbal region via targeted sub-limbal injection technique. Human cadaveric corneal tissues were fixed on an artificial anterior chamber. Feasibility of sub-limbal injection technique was tested using trypan blue and black India ink.

Spin state dependent peroxidase activity of heme bound amyloid β peptides relevant to Alzheimer's disease.

The colocalization of heme rich deposits in the senile plaque of Aβ in the cerebral cortex of the Alzheimer's disease (AD) brain along with altered heme homeostasis and heme deficiency symptoms in AD patients has invoked the association of heme in AD pathology. Heme bound Aβ complexes, depending on the concentration of the complex or peptide to heme ratio, exhibit an equilibrium between a high-spin mono-His bound peroxidase-type active site and a low-spin bis-His bound cytochrome b type active site. The high-spin heme-Aβ complex shows higher peroxidase activity than free heme, where compound I is the reactive oxidant.

Second Sphere Interactions in Amyloidogenic Diseases.

Amyloids are protein aggregates bearing a highly ordered cross β structural motif, which may be functional but are mostly pathogenic. Their formation, deposition in tissues and consequent organ dysfunction is the central event in amyloidogenic diseases. Such protein aggregation may be brought about by conformational changes, and much attention has been directed toward factors like metal binding, post-translational modifications, mutations of protein etc.

Insights from Self-Assembled Aggregates of Amyloid β Peptides on Gold Surfaces.

Amyloid β (Aβ) peptides mutated at different positions using a cysteine moiety assemble on Au electrodes using the thiol functionality of cysteine. Self-assembled monolayers (SAMs) of Aβ on Au surfaces can act as abiological platforms that allow the mimicking of fibrils and oligomeric Aβ via the formation of controlled large and small peptide aggregates. These Aβ constructs bind with heme and Cu and exhibit different reactivities.

Interaction of ApoMyoglobin with Heme-hIAPP complex.

Human Islet Amyloid Polypeptide (hIAPP) or amylin, can bind heme and the resultant complexes are prone to generate partially reduced oxygen species (PROS). The formation of PROS and the related oxidative stress highlight the importance of Heme-hIAPP in the onset and development of Type 2 Diabetes mellitus (T2Dm) in humans. In this study, the interaction of Heme-hIAPP with apomyoglobin (ApoMb) has been investigated using a combination of spectroscopic and electrophoresis techniques.

A Small Molecule that Binds an RNA Repeat Expansion Stimulates Its Decay via the Exosome Complex.

Many diseases are caused by toxic RNA repeats. Herein, we designed a lead small molecule that binds the structure of the r(CUG) repeat expansion [r(CUG)] that causes myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD) and rescues disease biology in patient-derived cells and in vivo. Interestingly, the compound's downstream effects are different in the two diseases, owing to the location of the repeat expansion.

Peroxidase activity of heme bound amyloid β peptides associated with Alzheimer's disease.

The amyloid cascade hypothesis attributes the neurodegeneration observed in Alzheimer's disease (AD) to the deposition of the amyloid β (Aβ) peptide into plaques and fibrils in the AD brain. The metal ion hypothesis which implicates several metal ions, viz. Zn, Cu and Fe, in the AD pathology on account of their abnormal accumulation in the Aβ plaques along with an overall dyshomeostasis of these metals in the AD brain was proposed a while back.

Formation of compound I in heme bound Aβ-peptides relevant to Alzheimer's disease.

Proteolysis of Amyloid Precursor Protein, APP, results in the formation of amyloid β (Aβ) peptides, which have been associated with Alzheimer's disease (AD). Recently the failure of therapeutic agents that prohibit Aβ aggregation and sequester Cu/Zn in providing symptomatic relief to AD patients has questioned the amyloid and metal ion hypothesis. Alternatively, abnormal heme homeostasis and reduced levels of neurotransmitters in the brain are hallmark features of AD.

Active-site environment of Cu bound amyloid β and amylin peptides.

Alzheimer's disease (AD) and Type 2 Diabetes mellitus (T2Dm), two of the most common amyloidogenic diseases. They share a common pathological symptom, i.e.

Nitrite reductase activity of heme and copper bound Aβ peptides.

A significant abundance of copper (Cu) and iron in amyloid β (Aβ) plaques, and several heme related metabolic disorders are directly correlated with Alzheimer's disease (AD), and these together with co-localization of Aβ plaques with heme rich deposits in the brains of AD sufferers indicates a possible association of the said metals with the disease. Recently, the Aβ peptides have been found to bind heme and Cu individually as well as simultaneously. Another significant finding relevant to this is the lower levels of nitrite and nitrate found in the brains of patients suffering from AD.

Parkin suppresses Drp1-independent mitochondrial division.

The cycle of mitochondrial division and fusion disconnect and reconnect individual mitochondria in cells to remodel this energy-producing organelle. Although dynamin-related protein 1 (Drp1) plays a major role in mitochondrial division in cells, a reduced level of mitochondrial division still persists even in the absence of Drp1. It is unknown how much Drp1-mediated mitochondrial division accounts for the connectivity of mitochondria.

CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis.

CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the "mitochondrial contact site and cristae organizing system" (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization.

PARK2/Parkin becomes critical when DNM1L/Drp1 is absent.

Maintaining mitochondrial dynamics and proper execution of mitophagy is crucial for sustaining cellular health. Defects in these processes have been linked to cardiovascular diseases and neurodegeneration. In a recent publication, we reported that the mitochondrial division dynamin protein DNM1L/Drp1 and the E3 ubiquitin ligase PARK2/Parkin work in a synergistic manner to maintain mitochondrial function and structural integrity in the mouse heart and brain.

Mitochondrial division and fusion in metabolism.

Mitochondria govern many metabolic processes. In addition, mitochondria sense the status of metabolism and change their functions to regulate energy production, cell death, and thermogenesis. Recent studies have revealed that mitochondrial structural remodeling through division and fusion is critical to the organelle's function.

Biosynthesis and roles of phospholipids in mitochondrial fusion, division and mitophagy.

Mitochondria move, fuse and divide in cells. The dynamic behavior of mitochondria is central to the control of their structure and function. Three conserved mitochondrial dynamin-related GTPases (i.

Physiological, anatomical, and behavioral changes after acoustic trauma in Drosophila melanogaster.

Noise-induced hearing loss (NIHL) is a growing health issue, with costly treatment and lost quality of life. Here we establish Drosophila melanogaster as an inexpensive, flexible, and powerful genetic model system for NIHL. We exposed flies to acoustic trauma and quantified physiological and anatomical effects.

Cbl-associated protein regulates assembly and function of two tension-sensing structures in Drosophila.

Cbl-associated protein (CAP) localizes to focal adhesions and associates with numerous cytoskeletal proteins; however, its physiological roles remain unknown. Here, we demonstrate that Drosophila CAP regulates the organization of two actin-rich structures in Drosophila: muscle attachment sites (MASs), which connect somatic muscles to the body wall; and scolopale cells, which form an integral component of the fly chordotonal organs and mediate mechanosensation. Drosophila CAP mutants exhibit aberrant junctional invaginations and perturbation of the cytoskeletal organization at the MAS.

Cell-type-specific roles of Na+/K+ ATPase subunits in Drosophila auditory mechanosensation.

Ion homeostasis is a fundamental cellular process particularly important in excitable cell activities such as hearing. It relies on the Na(+)/K(+) ATPase (also referred to as the Na pump), which is composed of a catalytic α subunit and a β subunit required for its transport to the plasma membrane and for regulating its activity. We show that α and β subunits are expressed in Johnston's organ (JO), the Drosophila auditory organ.