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Optimizing Crispr/Cas9 For Gene Silencing Of Sod1 In Mouse Models Of Als, Zachary C. Kennedy Aug 2019

Optimizing Crispr/Cas9 For Gene Silencing Of Sod1 In Mouse Models Of Als, Zachary C. Kennedy

GSBS Dissertations and Theses

Mutations in the SOD1 gene are the best characterized genetic cause of amyotrophic lateral sclerosis (ALS) and account for ~20% of inherited cases and 1-3% of sporadic cases. The gene-editing tool Cas9 can silence mutant genes that cause disease, but effective delivery of CRISPR-Cas9 to the central nervous system (CNS) remains challenging. Here, I developed strategies using canonical Streptococcus pyogenes Cas9 to silence SOD1. In the first strategy, I demonstrate effectiveness of systemic delivery of guide RNA targeting SOD1 to the CNS in a transgenic mouse model expressing human mutant SOD1 and Cas9. Silencing was observed in both the brain ...


Gene Therapy For Amyotrophic Lateral Sclerosis: An Aav Mediated Rnai Approach For Autosomal Dominant C9orf72 Associated Als, Gabriela Toro Mar 2019

Gene Therapy For Amyotrophic Lateral Sclerosis: An Aav Mediated Rnai Approach For Autosomal Dominant C9orf72 Associated Als, Gabriela Toro

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease that affects motor neurons causing progressive muscle weakness and respiratory failure. In 2011, the presence of a hexanucleotide repeat expansion within chromosome 9 open reading frame 72(C9ORF72) was identified in ALS patient samples, becoming the major known genetic cause for ALS and frontotemporal dementia (FTD). Carriers of this mutation present reduced levels of C9ORF72 mRNA, RNA foci produced by the aggregating expansion and toxic dipeptides generated through repeat-associated non-ATG translation. These findings have led to multiple hypotheses on the pathogenesis of C9ORF72: 1) Haploinsufficiency, 2) RNA gain-of-function, 3) RAN Translation ...


Fus And Excitotoxicity Cross Paths In Als: New Insights Into Cellular Stress And Disease, Maeve Tischbein Aug 2018

Fus And Excitotoxicity Cross Paths In Als: New Insights Into Cellular Stress And Disease, Maeve Tischbein

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease characterized by motor neuron loss. Although pathological mutations exist in >15 genes, the mechanism(s) underlying ALS are unknown. FUS is one such gene and encodes the nuclear RNA-binding protein (RBP), fused in sarcoma (FUS), which actively shuttles between the nucleus and cytoplasm. Intriguingly, nearly half of the ALS mutations identified in FUS cause this protein to mislocalize, suggesting that FUS localization is relevant to disease.

Here, we found that excitotoxicity, a neuronal stress caused by aberrant glutamate signaling, induces the rapid redistribution of FUS and additional disease-linked RBPs ...


Identification Of Novel Genetic Variations For Amyotrophic Lateral Sclerosis (Als), Guang Xu Feb 2018

Identification Of Novel Genetic Variations For Amyotrophic Lateral Sclerosis (Als), Guang Xu

GSBS Dissertations and Theses

A list of genes have been identified to carry mutations causing familial ALS such as SOD1, TARDBP, C9orf72. But for sporadic ALS, which is 90% of all ALS cases, the underlying genetic variants are still largely unknown. There are multiple genome-wide association study (GWAS) for sporadic ALS, but usually a large number nominated SNP can hardly be replicated in larger cohort analysis. Also majority of GWAS SNP lie within noncoding region of genome, imposing a huge challenge to study their biological role in ALS pathology. With the rapid development of next-generation sequencing technology, we are able to sequence exome and ...


Astrocytic Regulation Of Seizure-Like Behavior, Sukhee Cho Dec 2017

Astrocytic Regulation Of Seizure-Like Behavior, Sukhee Cho

GSBS Dissertations and Theses

Astrocytes are emerging as important regulators of neural circuit function and behavior in the healthy and diseased nervous system. In a screen for astrocyte molecules that modulate neuronal hyperexcitability we identified multiple components of focal adhesion complexes (FAs) as potent suppressors of genetically- or pharmacologically-induced seizure-like activity. Depletion of astrocytic Tensin, b-integrin, Talin, Focal adhesion kinase (FAK), or matrix metalloproteinase 1 (Mmp1), which degrades extracellular matrix to activate b-integrin receptors, resulted in enhanced recovery from, or resistance to seizure activity. Reciprocally, promoting FA signaling by overexpression of Mmp1 in astrocytes led to enhanced-seizure severity. Blockade of FA signaling in astrocytes ...


Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster Aug 2017

Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster

GSBS Dissertations and Theses

Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends ...


Inhibiting Axon Degeneration In A Mouse Model Of Acute Brain Injury Through Deletion Of Sarm1, Nils Henninger May 2017

Inhibiting Axon Degeneration In A Mouse Model Of Acute Brain Injury Through Deletion Of Sarm1, Nils Henninger

GSBS Dissertations and Theses

Traumatic brain injury (TBI) is a leading cause of disability worldwide. Annually, 150 to 200/1,000,000 people become disabled as a result of brain trauma. Axonal degeneration is a critical, early event following TBI of all severities but whether axon degeneration is a driver of TBI remains unclear. Molecular pathways underlying the pathology of TBI have not been defined and there is no efficacious treatment for TBI.

Despite this significant societal impact, surprisingly little is known about the molecular mechanisms that actively drive axon degeneration in any context and particularly following TBI. Although severe brain injury may cause ...


Overcoming Toxicity From Transgene Overexpression Through Vector Design In Aav Gene Therapy For Gm2 Gangliosidoses, Diane L. Golebiowski Sep 2016

Overcoming Toxicity From Transgene Overexpression Through Vector Design In Aav Gene Therapy For Gm2 Gangliosidoses, Diane L. Golebiowski

GSBS Dissertations and Theses

GM2 gangliosidoses are a family of lysosomal storage disorders that include both Tay-Sachs and Sandhoff diseases. These disorders result from deficiencies in the lysosomal enzyme β-N-acetylhexosaminidase (HexA). Impairment of HexA leads to accumulation of its substrate, GM2 ganglioside, in cells resulting in cellular dysfunction and death. There is currently no treatment for GM2 gangliosidoses. Patients primarily present with neurological dysfunction and degeneration. Here we developed a central nervous system gene therapy through direct injection that leads to long-term survival in the Sandhoff disease mouse model. We deliver an equal mixture of AAVrh8 vectors that encode for the two subunits (α ...


The Drosophila Homolog Of The Intellectual Disability Gene Acsl4 Acts In Glia To Regulate Morphology And Neuronal Activity: A Dissertation, Caitlin M. Quigley Jul 2016

The Drosophila Homolog Of The Intellectual Disability Gene Acsl4 Acts In Glia To Regulate Morphology And Neuronal Activity: A Dissertation, Caitlin M. Quigley

GSBS Dissertations and Theses

Recent developments in neurobiology make it clear that glia play fundamental and active roles, in the adult and in development. Many hereditary cognitive disorders have been linked to developmental defects, and in at least two cases, Rett Syndrome and Fragile X Mental Retardation, glia are important in pathogenesis. However, most studies of developmental disorders, in particular intellectual disability, focus on neuronal defects. An example is intellectual disability caused by mutations in ACSL4, a metabolic enzyme that conjugates long-chain fatty acids to Coenzyme A (CoA). Depleting ACSL4 in neurons is associated with defects in dendritic spines, a finding replicated in patient ...


Functional Characterization Of Novel Pfn1 Mutations Causative For Familial Amyotrophic Lateral Sclerosis: A Dissertation, Chi-Hong Wu Dec 2015

Functional Characterization Of Novel Pfn1 Mutations Causative For Familial Amyotrophic Lateral Sclerosis: A Dissertation, Chi-Hong Wu

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is a progressive adult neurodegenerative disease that causes death of both upper and lower motor neurons. Approximately 90 percent of ALS cases are sporadic (SALS), and 10 percent are inherited (FALS). Mutations in the PFN1 gene have been identified as causative for one percent of FALS. PFN1 is a small actin-binding protein that promotes actin polymerization, but how ALS-linked PFN1 mutations affect its cognate functions or acquire gain-of-function toxicity remains largely unknown.

To elucidate the contribution of ALS-linked PFN1 mutations to neurodegeneration, we have characterized these mutants in both mammalian cultured cells and Drosophila models. In ...


Gene Therapy For Amyotrophic Lateral Sclerosis: An Aav Delivered Artifical Microrna Against Human Sod1 Increases Survival And Delays Disease Progression Of The Sod1G93a Mouse Model: A Dissertation, Lorelei I. Stoica Dec 2015

Gene Therapy For Amyotrophic Lateral Sclerosis: An Aav Delivered Artifical Microrna Against Human Sod1 Increases Survival And Delays Disease Progression Of The Sod1G93a Mouse Model: A Dissertation, Lorelei I. Stoica

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons, resulting in progressive muscle weakness, atrophy, paralysis and death within five years of diagnosis. About ten percent of cases are inherited, of which twenty percent are due to mutations in the superoxide dismutase 1 (SOD1) gene. Since the only FDA approved ALS drug prolongs survival by just a few months, new therapies for this disease are needed. Experiments in transgenic ALS mouse models have shown that decreasing levels of mutant SOD1 protein alters and in some cases entirely prevents disease progression. We explored this potential ...


The Role Of Vta Gabaergic Nicotinic Acetylcholine Receptors Containing The Α4 Subunit In Nicotine Dependence: A Dissertation, Jennifer Ngolab Oct 2015

The Role Of Vta Gabaergic Nicotinic Acetylcholine Receptors Containing The Α4 Subunit In Nicotine Dependence: A Dissertation, Jennifer Ngolab

GSBS Dissertations and Theses

Nicotine dependence is hypothesized to be due to neuroadaptations that ultimately drive compulsive nicotine use. The studies in this thesis aim to understand how the “upregulation” of nicotinic acetylcholine receptors (nAChRs) caused by chronic exposure to nicotine contributes to nicotine reward and nicotine withdrawal. Previous studies have shown that chronic nicotine induces upregulation of nAChRs containing the α4 subunit (α4* nAChR) within the Ventral Tegmental Area (VTA), a brain region critical for the rewarding properties of all illicit drugs. Curiously, α4* nAChR upregulation occurs specifically in the inhibitory GABAergic neuronal subpopulation of the VTA. To determine if increased expression and ...


Exploring The Role Of Fus Mutants From Stress Granule Incorporation To Nucleopathy In Amyotrophic Lateral Sclerosis: A Dissertation, Hae Kyung Ko Sep 2015

Exploring The Role Of Fus Mutants From Stress Granule Incorporation To Nucleopathy In Amyotrophic Lateral Sclerosis: A Dissertation, Hae Kyung Ko

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by preferential motor neuron death in the brain and spinal cord. The rapid disease progression results in death due to respiratory failure, typically within 3-5 years after disease onset. While ~90% of cases occur sporadically, remaining 10% of ALS cases show familial inheritance, and the number of genes linked to ALS has increased dramatically over the past decade.

FUS/TLS (Fused in Sarcoma/ Translocated to liposarcoma) is a nucleic acid binding protein that may regulate several cellular functions, including RNA splicing, transcription, DNA damage repair and microRNA biogenesis. More than ...


Investigating The Effects Of Mutant Fus On Stress Response In Amyotrophic Lateral Sclerosis: A Thesis, Laura J. Kaushansky Aug 2015

Investigating The Effects Of Mutant Fus On Stress Response In Amyotrophic Lateral Sclerosis: A Thesis, Laura J. Kaushansky

GSBS Dissertations and Theses

During stress, eukaryotes regulate protein synthesis in part through formation of cytoplasmic, non-membrane-bound complexes called stress granules (SGs). SGs transiently store signaling proteins and stalled translational complexes in response to stress stimuli (e.g. oxidative insult, DNA damage, temperature shifts and ER dysfunction). The functional outcome of SGs is proper translational regulation and signaling, allowing cells to overcome stress.

The fatal motor neuron disease Amyotrophic Lateral Sclerosis (ALS) develops in an age-related manner and is marked by progressive neuronal death, with cytoplasmic protein aggregation, excitotoxicity and increased oxidative stress as major hallmarks. Fused in Sarcoma/Translocated in Liposarcoma (FUS) is ...


Identifying, Targeting, And Exploiting A Common Misfolded, Toxic Conformation Of Sod1 In Als: A Dissertation, Melissa S. Rotunno Jun 2015

Identifying, Targeting, And Exploiting A Common Misfolded, Toxic Conformation Of Sod1 In Als: A Dissertation, Melissa S. Rotunno

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a loss of voluntary movement over time, leading to paralysis and death. While 10% of ALS cases are inherited or familial (FALS), the majority of cases (90%) are sporadic (SALS) with unknown etiology. Approximately 20% of FALS cases are genetically linked to a mutation in the anti-oxidizing enzyme, superoxide dismutase (SOD1). SALS and FALS are clinically indistinguishable, suggesting a common pathogenic mechanism exists for both types. Since such a large number of genetic mutations in SOD1 result in FALS (>170), it is reasonable to suspect that non-genetic modifications to SOD1 ...


Approaches And Considerations Towards A Safe And Effective Adeno-Associated Virus Mediated Therapeutic Intervention For Gm1-Gangliosidosis: A Dissertation, Cara M. Weismann Aug 2014

Approaches And Considerations Towards A Safe And Effective Adeno-Associated Virus Mediated Therapeutic Intervention For Gm1-Gangliosidosis: A Dissertation, Cara M. Weismann

GSBS Dissertations and Theses

GM1 gangliosidosis is a lysosomal storage disorder caused by a deficiency in the catabolizing enzyme β-galactosidase (βgal). This leads to accumulation of GM1-ganglioside (GM1) in the lysosome inducing ER stress and cell death. GM1 gangliosidosis is primarily a disorder of the central nervous system (CNS) with peripheral organ involvement. In this work we report two major findings, 1) systemic treatment of GM1 gangliosidosis with an adenoassociated virus (AAV9) encoding mouse-βgal (mβgal) in a GM1 gangliosidosis mouse model (βGal-/-), and 2) an investigation into an intracranial injection of a therapeutic AAVrh8 encoding mβgal. Systemic treatment of GM1 gangliosidosis with AAV9 resulted ...


The Cellular Consequences Of Fus/Tls Depletion: A Loss Of Function Model For Amyotrophic Lateral Sclerosis: A Dissertation, Catherine L. Ward Jul 2014

The Cellular Consequences Of Fus/Tls Depletion: A Loss Of Function Model For Amyotrophic Lateral Sclerosis: A Dissertation, Catherine L. Ward

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons, generally leading to paralysis and death within 3-5 years of onset. Over 50 different mutations in the gene encoding FUS/TLS (or FUS) will result in ALS, accounting for ~4% of all inherited cases. FUS is a multifunctional protein with important functions in DNA/RNA processing and stress response. How these mutations affect the structure or function of FUS protein and ultimately cause ALS is not known. The fact that mutations cause the protein to mislocalize from the nucleus to the cytoplasm of cells ...


Adhd-200 Patient Characterization And Classification Using Resting State Networks: A Dissertation, Suzanne M. Czerniak Mar 2014

Adhd-200 Patient Characterization And Classification Using Resting State Networks: A Dissertation, Suzanne M. Czerniak

GSBS Dissertations and Theses

Attention Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder of childhood that is characterized by symptoms of inattention, impulsivity/hyperactivity, or a combination of both. Intrinsic brain dysfunction in ADHD can be examined through various methods including resting state functional Magnetic Resonance Imaging (rs-fMRI), which investigates patients’ functional brain connections in the absence of an explicit task. To date, studies of group differences in resting brain connectivity between patients with ADHD and typically developing controls (TDCs) have revealed reduced connectivity within the Default Mode Network (DMN), a resting state network implicated in introspection, mind-wandering, and day-dreaming. However, few studies ...


From Neurodegeneration To Infertility And Back - Exploring Functions Of Two Genes: Armc4 And Tardbp: A Dissertation, Wei Cheng Jan 2014

From Neurodegeneration To Infertility And Back - Exploring Functions Of Two Genes: Armc4 And Tardbp: A Dissertation, Wei Cheng

GSBS Dissertations and Theses

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset progressive neurodegenerative disease that causes degeneration in both upper and lower motor neurons. ALS progresses relentlessly after the onset of the disease, with most patients die within 3-5 years of diagnosis, largely due to respiratory failure. Since SOD1 became the first gene whose mutations were associated with ALS in 1993, more than 17 ALS causative genes have been identified. Among them, TAR DNA-binding protein (TARDBP) lies in the central of ALS pathology mechanism study, because TDP43 proteinopathy is observed not only in familial ALS cases carrying TARDBP mutations, but also in most of ...


A Role For Neuronal Nicotinic Acetylcholine Receptors In Dopamine-Mediated Behaviors And The Hypnotic Response To Anesthetics: A Dissertation, Lindsey G. Soll Dec 2013

A Role For Neuronal Nicotinic Acetylcholine Receptors In Dopamine-Mediated Behaviors And The Hypnotic Response To Anesthetics: A Dissertation, Lindsey G. Soll

GSBS Dissertations and Theses

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels that most notably influence dopamine (DA) release. In this thesis, I examine the role of nAChRs in mediating DA-related behaviors such as movement and drug dependence. To accomplish this, I utilized a “gain-offunction” knock-in mouse (the Leu9’Ala line) containing agonist-hypersensitive α4* nAChRs (* indicates other nAChR subunits in addition to α4 are within the receptor complex) that renders receptors 50-fold more sensitive to nicotine and acetylcholine than wild-type (WT) receptors. I found that DHβE, a selective antagonist for α4β2* nAChRs, induced reversible and robust motor dysfunction characterized by hypolocomotion, akinesia, catalepsy ...


Dynamic Regulation At The Neuronal Plasma Membrane: Novel Endocytic Mechanisms Control Anesthetic-Activated Potassium Channels And Amphetamine-Sensitive Dopamine Transporters: A Dissertation, Luke R. Gabriel Jun 2013

Dynamic Regulation At The Neuronal Plasma Membrane: Novel Endocytic Mechanisms Control Anesthetic-Activated Potassium Channels And Amphetamine-Sensitive Dopamine Transporters: A Dissertation, Luke R. Gabriel

GSBS Dissertations and Theses

Endocytic trafficking dynamically regulates neuronal plasma membrane protein presentation and activity, and plays a central role in excitability and plasticity. Over the course of my dissertation research I investigated endocytic mechanisms regulating two neuronal membrane proteins: the anesthetic-activated potassium leak channel, KCNK3, as well as the psychostimulant-sensitive dopamine transporter (DAT). My results indicate that KCNK3 internalizes in response to Protein Kinase C (PKC) activation, using a novel pathway that requires the phosphoserine binding protein, 14-3-3β, and demonstrates for the first time regulated KCNK3 channel trafficking in neurons. Additionally, PKC-mediated KCNK3 trafficking requires a non-canonical endocytic motif, which is shared exclusively ...


The Study Of Two Strategies For Decreasing Mutant Huntingtin: Degradation By Puromycin Sensitive Aminopeptidase And Rna Interference: A Dissertation, Joanna Chaurette May 2013

The Study Of Two Strategies For Decreasing Mutant Huntingtin: Degradation By Puromycin Sensitive Aminopeptidase And Rna Interference: A Dissertation, Joanna Chaurette

GSBS Dissertations and Theses

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the huntingtin gene, resulting in an expanded polyglutamine (polyQ) repeat in the huntingtin protein. Patients receive symptomatic treatment for motor, emotional, and cognitive impairments; however, there is no treatment to slow the progression of the disease, with death occurring 15-20 years after diagnosis. Mutant huntingtin protein interferes with multiple cellular processes leading to cellular dysfunction and neuronal loss. Due to the complexity of mutant huntingtin toxicity, many approaches to treating each effect are being investigated. Unfortunately, addressing one cause of toxicity ...


Glial Control Of Synapse Assembly At The Drosophila Neuromuscular Junction: A Dissertation, Kimberly S. Kerr Sep 2012

Glial Control Of Synapse Assembly At The Drosophila Neuromuscular Junction: A Dissertation, Kimberly S. Kerr

GSBS Dissertations and Theses

Emerging evidence in both vertebrates and invertebrates is redefining glia as active and mobile players in synapse formation, maturation and function. However, the molecular mechanisms through which neurons and glia interact with each other to regulate these processes is not well known. My thesis work begins to understand how glia use secreted factors to modulate synaptic function. We use Drosophila melanogaster, a simple and genetically tractable model system, to understand the molecular mechanisms by which glia communicate with neurons at glutamatergic neuromuscular junctions (NMJs). We previously showed that a specific subtype of glia, subperineurial peripheral glia cells (SPGs), establish dynamic ...


A Novel Communication Mechanism Between The Presynapse And Postsynapse Through Exosomes: A Dissertation, Ceren Korkut Aug 2012

A Novel Communication Mechanism Between The Presynapse And Postsynapse Through Exosomes: A Dissertation, Ceren Korkut

GSBS Dissertations and Theses

The minimal element of the nervous system, the synapse, is a plastic structure that has the ability to change in response to various internal and external factors. This property of the synapse underlies complex behaviors such as learning and memory. However, the exact molecular and cellular mechanisms involved in this process are not fully understood. To understand the mechanisms that regulate synapse development and plasticity I took advantage of a powerful model system, the Drosophila larval neuromuscular junction (NMJ). In this system, both anterograde and retrograde signaling pathways critical for coordinated synapse development and plasticity have been documented.

An anterograde ...


Maintaining The Balance: Coordinating Excitation And Inhibition In A Simple Motor Circuit: A Dissertation, Hilary A. Petrash Aug 2012

Maintaining The Balance: Coordinating Excitation And Inhibition In A Simple Motor Circuit: A Dissertation, Hilary A. Petrash

GSBS Dissertations and Theses

The generation of complex behaviors often requires the coordinated activity of diverse sets of neural circuits in the brain. Activation of neuronal circuits drives behavior. Inappropriate signaling can contribute to cognitive disorders such as epilepsy, Parkinson’s, and addiction (Nordberg et al., 1992; Quik and McIntosh, 2006; Steinlein et al., 2012). The molecular mechanisms by which the activity of neural circuits is coordinated remain unclear. What are the molecules that regulate the timing of neural circuit activation and how is signaling between various neural circuits achieved? While much work has attempted to address these points, answers to these questions have ...


Therapeutic Silencing Of Mutant Huntingtin By Targeting Single Nucleotide Polymorphisms: A Dissertation, Edith L. Pfister Jul 2012

Therapeutic Silencing Of Mutant Huntingtin By Targeting Single Nucleotide Polymorphisms: A Dissertation, Edith L. Pfister

GSBS Dissertations and Theses

Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder. Invariably fatal, HD is caused by expansion of the CAG repeat region in exon 1 of the Huntingtin gene which creates a toxic protein with an extended polyglutamine tract 1. Silencing mutant Huntingtin messenger RNA (mRNA) is a promising therapeutic approach 2-6. The ideal silencing strategy would reduce mutant Huntingtin while leaving the wild-type mRNA intact. Unfortunately, targeting the disease causing CAG repeat expansion is difficult and risks targeting other CAG repeat containing genes.

We examined an alternative strategy, targeting single nucleotide polymorphisms (SNPs) in the Huntingtin mRNA. The ...


Eaters Of The Dead: How Glial Cells Respond To And Engulf Degenerating Axons In The Cns: A Dissertation, Jennifer S. Ziegenfuss Jun 2012

Eaters Of The Dead: How Glial Cells Respond To And Engulf Degenerating Axons In The Cns: A Dissertation, Jennifer S. Ziegenfuss

GSBS Dissertations and Theses

Glia, whose name derives from the original Greek word, meaning “glue,” have long been understood to be cells that play an important functional role in the nutritive and structural support of the central nervous system, yet their full involvement has been historically undervalued. Despite the strong evidence that glial reactions to cellular debris govern the health of the nervous system, the specific properties of damaged axonal debris and the mechanisms by which glia sense them, morphologically adapt to their presence, and initiate phagocytosis for clearance, have remained poorly understood. The work presented in this thesis was aimed at addressing this ...


A Role For C-Jun Kinase (Jnk) Signaling In Glial Engulfment Of Degenerating Axons: A Dissertation, Jennifer M. Macdonald Jun 2012

A Role For C-Jun Kinase (Jnk) Signaling In Glial Engulfment Of Degenerating Axons: A Dissertation, Jennifer M. Macdonald

GSBS Dissertations and Theses

The central nervous system (CNS) is composed of two types of cells: neurons that send electrical signals to transmit information throughout the animal and glial cells. Glial cells were long thought to be merely support cells for the neurons; however, recent work has identified many critical roles for these cells during development and in the mature animal. In the CNS, glial cells act as the resident immune cell and they are responsible for the clearance of dead or dying material. After neuronal injury or death, glial cells become reactive, exhibiting dramatic changes in morphology and patterns of gene expression and ...


Transposition Driven Genomic Heterogeneity In The Drosophila Brain: A Dissertation, Paola N. Perrat Jun 2012

Transposition Driven Genomic Heterogeneity In The Drosophila Brain: A Dissertation, Paola N. Perrat

GSBS Dissertations and Theses

In the Drosophila brain, memories are processed and stored in two mirrorsymmetrical structures composed of approximately 5,000 neurons called Mushroom Bodies (MB). Depending on their axonal extensions, neurons in the MB can be further classified into three different subgroups: αβ, α’β’ and γ. In addition to the morphological differences between these groups of neurons, there is evidence of functional differences too. For example, it has been previously shown that while neurotransmission from α’β’ neurons is required for consolidation of olfactory memory, output from αβ neurons is required for its later retrieval. To gain insight into the functional ...


Molecular Mechanisms Of Endocytosis: Trafficking And Functional Requirements For The Transferrin Receptor, Small Interfering Rnas And Dopamine Transporter: A Dissertation, Deanna M. Navaroli Apr 2012

Molecular Mechanisms Of Endocytosis: Trafficking And Functional Requirements For The Transferrin Receptor, Small Interfering Rnas And Dopamine Transporter: A Dissertation, Deanna M. Navaroli

GSBS Dissertations and Theses

Endocytosis is an essential function of eukaryotic cells, providing crucial nutrients and playing key roles in interactions of the plasma membrane with the environment. The classical view of the endocytic pathway, where vesicles from the plasma membrane fuse with a homogenous population of early endosomes from which cargo is sorted, has recently been challenged by the finding of multiple subpopulations of endosomes. These subpopulations vary in their content of phosphatidylinositol 3- phosphate (PI3P) and Rab binding proteins. The role of these endosomal subpopulations is unclear, as is the role of multiple PI3P effectors, which are ubiquitously expressed and highly conserved ...