Genetic Processes Commons^™

Missense Mutations In The Snca Gene: Molecular Mechanisms And Clinical Implications, Pranaya Gade, Nishant Patel, Jamir Pitton Rissardo, Jorge Patino, Ana Fornari-Caprara, Ian Walker

Rowan-Virtua Research Day

The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence …

Fos Expression In Lateral Hypothalamus/Perifornical Area Is Correlated With Psychosocial Stress-Induced Cocaine-Seeking Behavior In A Sex-Specific Manner, Milena Sudarikov, Nicole M. Hinds, Ireneusz D. Wojtas, Desta M. Pulley, Daniel F. Manvich

Rowan-Virtua Research Day

Cocaine Use Disorder persists as a significant public health concern in the United States. Recent epidemiological data indicate that rates of cocaine-involved overdose deaths are rising, and treatment of Cocaine Use Disorder is challenging due to a lack of FDA-approved medications to help patients achieve abstinence and avoid relapse. Stress can precipitate cocaine craving and trigger relapse episodes, however the underlying neural circuitry by which stressors drive cocaine seeking is not completely understood. Our laboratory has recently identified the potential involvement of the rostrolateral aspect of the periaqueductal gray (rlPAG) in psychosocial stress-induced cocaine-seeking behavior using a rodent model of …

Differential Degeneration Of Neurons In A Mouse Model Of Canavan Disease, Vibha Chauhan, Quy Nguyen, Jeremy Francis, Paola Leone

Rowan-Virtua Research Day

Canavan disease (CD) is an inherited leukodystrophy caused by inactivating mutations to the glial enzyme aspartoacylase (ASPA). ASPA catabolizes neuronal N-acetylaspartate (NAA) into free acetate and aspartate and loss of this function results in the chronic elevation of non-catabolized NAA and the failure of developmental myelination. Elevated NAA is thought to cause damage to myelin and myelin-producing cells (oligodendrocytes, but the viability of neurons in CD is relatively unexplored. We compare here the progressive degeneration of neurons in two regions of the CD mouse brain, the thalamus and the cortex, distinguished by differing degrees of vacuolation, and show that the …

Orthologs Of The C. Elegans Heterochronic Genes Have Divergent Functions In C. Briggsae, Maria Ivanova, Eric G. Moss

Rowan-Virtua Research Day

The heterochronic genes of C. elegans comprise the best-studied pathway controlling the timing of tissue and organ formation in an animal. To begin to understand the evolution of this pathway, the significance of each factor, and the relationships among the components, we characterized 11 C. briggsae orthologs of C. elegans heterochronic genes. Using CRISPR/Cas9, we made a variety of alleles and found that several mutant phenotypes differ in significant ways from those of C. elegans. Although most orthologs displayed defects in developmental timing, those phenotypes could differ in which stages they controlled, the penetrance and expressivity of the phenotypes, or …

Conservation And Divergence In The Heterochronic Pathway Of C. Elegans And C. Briggsae, Maria Ivanova, Eric G. Moss

Rowan-Virtua Research Day

The heterochronic pathway of Caenorhabditis elegans is exemplary as a mechanism of developmental timing: mutations in genes of this pathway alter the relative timing of diverse developmental events independent of spatial or cell type specific regulation. It is the most thoroughly characterized developmental timing pathway known. Most of the heterochronic genes are conserved across great evolutionary time, and a few homologs seem to have developmental timing roles in certain contexts. The degree to which other organisms have explicit developmental timing mechanisms, and what factors comprise those mechanisms, isn’t generally known.

Developmental pathways evolve even if the resulting morphology remains the …

Modeling The Role Of Cyclin C In Connecting Stress-Induced Mitochondrial Fission To Apoptosis, Steven J. Doyle, Randy Strich

Rowan-Virtua Research Day

For normal cell function, exogenous signals must be correctly interpreted, and the proper response executed. The mitochondria are key regulatory nodes of cellular fate. For example, mitochondria undergo fission and fusion cycles depending on the energetic needs of the cell. Additionally, regulated cell death pathways also function at the mitochondria. Cyclin C is a transcriptional regulator of stress response and growth control genes. Following stress, a portion of cyclin C translocates to the cytoplasm, where it interacts with both the mitochondrial fission and apoptotic machinery. Based on these findings, we hypothesize that Cyclin C represents a key mediator linking transcription …

Substrate-Specific Effect On Sirtuin Conformation And Oligomerization, Jie Yang, Shannon L. Dwyer, Nathan I. Nicely, Brian P. Weiser

Rowan-Virtua Research Day

Human sirtuins are a family of nicotinamide adenine dinucleotide (NAD +)-dependent enzymes that are responsible for removing acyl modifications from lysine residues. Sirtuins are involved in the formation and proliferation of cancers and are thought to regulate the progression of neurodegenerative diseases. Although sirtuins can be pharmacologically targeted by small molecules, it is not easy to modulate the substrate selectivity of sirtuins despite the chemical diversity of their substrates. Here, we report substrate-specific effects on sirtuin conformation and oligomerization that regulate enzyme deacylase activity. We used fluorescent acyl peptide probes to study substrate interactions with two sirtuin isoforms: SIRT2 and …

Ung2 And Rpa Activity On Ssdna-Dsdna Junctions, Kathy Chen, Sharon Greenwood, Brian P. Weiser

Rowan-Virtua Research Day

Uracil DNA glycosylase, or UNG2, is an enzyme that is involved in DNA repair. Its primary job is to eliminate harmful uracil bases from DNA strands. To do this, the enzyme is assisted by replication protein A (RPA). RPA helps UNG2 in the identification of uracil bases by targeting UNG2 activity near ssDNA-dsDNA junctions (1-3). The results from assays presented here agree with published findings that showed UNG2 is heavily targeted by RPA to uracil bases that are close to ssDNA-dsDNA junctions (for example, uracil located 9 bps from the junction as opposed to 33 bps) (1,2). However, these previous …

Replication Protein A (Rpa) Targeting Of Uracil Dna Glycosylase (Ung2), Derek Chen, Brian P Weiser

Rowan-Virtua Research Day

Replication Protein A (RPA) is a single stranded DNA binding protein which stabilizes ssDNA for replication and repair. One function of RPA is to bind the DNA repair enzyme uracil DNA glycosylase (UNG2) and direct its activity towards ssDNA dsDNA junctions.

UNG2 removes uracil bases from DNA which can appear through dUMP misincorporation or through cytosine deamination. If uracil is present instead of a cytosine, then the original GC pair becomes a GU pair. The uracil will then base pair to adenine in the replicated daughter strand. This results in a GC → AT mutation that could contribute to cancer …