Ubiquilin (UBQLN) is a member of type2 ubiquitin-like (UBL) protein family characterized by an UBL domain at the N-terminus and an ubiquitin associated (UBA) domain at the C-terminus. This protein has been shown to play an important role in the regulation of the levels, aggregation and degradation of various neurodegenerative disease-associated proteins. However, the specific functions and mechanisms of UBQLN regulation still remain to be elucidated. In this study, we investigate the effect of UBQLN expression on α-Amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR) degradation and the underlying molecular mechanisms. We show that UBQLN overexpression decreases AMPAR levels in neurons and also reduces GluA1 expression in HEK 293T cells. Moreover, our results indicate that UBQLN can form a complex with GluA1, and this interaction is related to the ubiquitination of AMPARs. In addition, we find a higher expression of UBQLN2 in Alzheimer’s disease (AD) patient brains, which might be a potential pathological mechanism of GluA1 reduction in AD. Given the crucial effect of UBQLN in AMPAR regulation, UBQLN may play an important role in synaptic transmission, brain functions as well as neurodegenerative diseases. / 2018-07-21T00:00:00Z

Neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are increasingly common in our ageing society, are remain incurable. A major obstacle encountered by researchers in their attempts to find effective therapies is represented by the current lack of understanding of the molecular origins of these disorders. It is becoming clear that, although the aggregation of specific proteins, including amyloid β (Aβ) and tau in AD and α-synuclein in PD, hallmark these disorders, such behaviour is a consequence of a wider, system-level disruption of protein homeostasis. In order to identify the genetic factors contributing to such a disruption, the transcriptional changes that occur during neurodegenerative disease progression have received considerable scientific attention in recent years. In our approach, we considered another hallmark of these diseases - their characteristic patterns of spreading across the brain - to identify the nature of the transcriptional signature which underlies tissue vulnerability to protein aggregation. By understanding why tissues succumb in their characteristic sequential pattern in neurodegenerative diseases, and why some tissues remain almost completely resistant throughout, we hoped to obtain insight into the molecular origins of these disorders. Our results show that the AD progression can be predicted from a transcriptional signature in healthy brains related to the protein aggregation homeostasis of Aβ, tau, and the wider proteome. We highlight a relationship between a specific subproteome at high risk of aggregation (formed by supersaturated proteins), and the vulnerability to neurodegenerative diseases. We thus identify an AD-specific supersaturated set of proteins - termed the metastable subproteome, whose expression in normal brains recapitulates the staging of AD, with more vulnerable tissues having higher metastable subproteome expression. We find evidence of these vulnerability signatures transcending the tissue level of interrogation, with cellular and subcellular analysis also showing elevated levels of proteins known and predicted to predispose the aberrant aggregation of Aβ and tau. These results characterise the key protein homeostasis pathways in the inception and progression of AD, and establish an approach with the potential to be applied to other protein misfolding diseases, in the brain and beyond.

Histone deacetylase (HDAC) inhibitors (HDACIs) have long been studied and shown promises in the treatment of various neurodegenerative disorders including Huntington’s disease (HD). Based on many demonstrated potentials of HDACIs in mitigating various diseases, we evaluated the utility of [18F]FAHA, a radiolabeled derivative of suberoylanilide hydroxamic acid (SAHA), as a PET imaging agent for characterizing HDAC activity in a non-human primate model and a R6/2 transgenic mouse model of HD. We were aiming at HD as a potential first application, and therefore also examined the expression of HDAC and acetyl histone (AH) in brains of HD patients. This thesis describes that [18F]FAHA was metabolized rapidly to [18F]FACE in both blood plasma and brain. Kinetic analysis indicated that peripherally generated [18F]FACE contributed to the total brain activity. We therefore used a dual-input function model to analyze the kinetics of tracer accumulation and inhibition by SAHA in rhesus monkeys. Parametric images demonstrated the inhibition of HDAC activity in the brain by SAHA in a dose-dependent manner. Huntington’s mice (R6/2) showed a gradual increase of [18F]FAHA accumulation in all organs including the brain with age. In human tissue we found significant losses of acetyl histons expression from cells in the caudate nucleus and Purkinje cells of the cerebellum in HD, while the level of HDAC 5 was increased in these cells. The data obtained in rhesus monkeys indicated that PET imaging with [18F]FAHA could be used as a pharmacodynamic biomarker of the inhibition of class IIa HDACs by HDACIs in the brain and facilitate the development and clinical translation of novel class-IIa HDACIs.

Matrix Metalloproteinase-28 (MMP-28) is the newest and least characterized member of MMP family. To date several potential substrate candidates for MMP-28 have been proposed but no in vivo substrates for this enzyme were confirmed. In the central nervous system (CNS) MMP-28 is believed to be important factor during myelination of the developing nervous system as well as during remyelination that follows neuronal injury. On the other hand, MMP-28 has been found in actively demyelinating lesions in both experimental autoimmune encephalopathy (EAE) and multiple sclerosis patients suggesting its possible role in pathological events associated with autoimmune neurodegenerative processes. In addition, MMP-28 has been linked to modulation of immune response and activation of macrophages which presents another role of this enzyme in autoimmune pathologies. In the study described herein, MMP-28 has been shown to affect myelin composition and appearance, mitochondrial protein content, and vesicular transport proteins. Moreover, the decrease in myelin basic protein quantity observed in healthy MMP-28KO animals affected the myelin staining intensity in various brain regions including corpus callous. Cellular energetic studies did not reveal differences in mitochondrial function in MMP-28KO animals and no difference in reactive oxygen species was observed. In the EAE model, MMP-28 deletion increased the occurrence of atypical form of EAE characterized by increased inflammation of arbor vitae of the brain. In addition, MMP-28 deletion decreased the inflammatory infiltrates present in brains obtained from EAE animals. Lastly, MMP-28 has been shown to affect cellular energetics and activation of bone marrow derived macrophages during the initial stages and after 24 h activation. In addition, MMP-28 deletion increased proinflammatory cytokines and receptors CD86 and iNOS found in M1 polarized macrophages. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

Mitochondria not only supply the energy for cell function, but also take part in cell signaling. This review describes the dysfunctions of mitochondria in aging and neurodegenerative diseases, and the signaling pathways leading to mitochondrial biogenesis (including PGC-1 family proteins, SIRT1, AMPK) and mitophagy (parkin-Pink1 pathway). Understanding the regulation of these mitochondrial pathways may be beneficial in finding pharmacological approaches or lifestyle changes (caloric restrict or exercise) to modulate mitochondrial biogenesis and/or to activate mitophagy for the removal of damaged mitochondria, thus reducing the onset and/or severity of neurodegenerative diseases.

Advancements in Deep Neural Network Architectures have enabledit to be used in the medical imaging and diagnostics domain, in termsof assisting doctors in making diagnoses. Although Neurodegenera-tive diseases such as Alzheimer’s disease remains a diagnosis basedon clinical grounds, there has been great development and recogni-tion that Deep Neural Networks can address the complexity and vol-ume of imaging data.The purpose of our Master Thesis is to address this problem of theclassification of brain PET scans with 18F-FDG radioactive tracer andtheir interpretability. For the classification, four pre-trained networkswere picked. These networks were trained on ADNI data and theirresults were compared to find the best model. To address the prob-lem of interpretability a hybrid interpretability model was developed;a model based on the combination of t-SNE plots and Class Activa-tion Maps. The hybrid model gave an insight into both the atomisticand holistic working of the network. In the end, the interpretabilitymodel was reviewed by a radiologist to check its effectiveness in thepractical world.Among the four models, the best performing model was the Incep-tionResNetV2 as it highlighted the hypometabolism activity in thebrain regions that are crucial to the diagnosis of Alzheimer’s Diseaseand explained the cluster formation of the correctly classified cases. Itwas concluded that the hybrid explainability model, provided betterinterpretability as compared to the presented individual interpretabil-ity methods.

G-quadruplexes, a type of nucleic acid secondary structure consisting largely of folded quartets of guanines, appear to play a regulatory role in the human genome. Heme has been shown to interact with G-quadruplexes. The ChIP-Seq-like Heme-Seq assay was developed to identify heme binding G-quadruplex loci. Using Heme-Seq, 3 primary heme binding loci and 4 secondary minor heme binding loci were identified on six chromosomes. Two of the primary heme binding loci were found at the centromeric boundaries of the long arms of metacentric chromosomes with the majority of reads from the primary heme binding loci consisting primarly of Human Satellite II (HSATII) nucleotide repeat sequences. Numerous putative G-quadruplex forming sequences were found in the heme-binding locus on Chromosome 2. Comparison of Heme-Seq results with available data from a G-quadruplex ChIP-Seq study in live cells, revealed that the regions which exhibited binding at the three peaks from the Heme-Seq data also showed binding coverage in the CHIP-Seq data. In addition to the known association with G-quadruplexes, heme also appears to bind to HSATII repeats,. The biological role and importance of this binding is not known. / Biomedical Sciences

Dopamine (DA) is a catecholamine that is involved in several neural functions such as modulation of locomotor behaviors, arousal states to appetitive aversive learning and memory. The relationships between DA, stress response and aging are unclear. This thesis examines numerous physiological, behavioral and biochemical parameters following perturbations in DA synthesis and transport in the Drosophila melanogaster model system. Intriguingly, elevated DA pools appear to confer protection, while depleted DA levels or transport increase susceptibility to oxidative insult. Resistance to oxidative stress in mutants with elevated DA levels was attributed to a significant up-regulation of glutathione S-transferase Omega-1. A sexually dimorphic response in aging and senescence characteristics was also recorded among the mutants tested, but no discernable role of DA in these characteristics was observed. Taken together, these results point to a key role played by DA in stress response, which might have implications to age-related neurodegenerative diseases.

Alzheimer’s disease is a neurodegenerative disorder characterized by symptoms such as memory loss and behavioral change, and it is the sixth leading cause of death in the U.S. This literature-based thesis aims to detail the history of the disease as well as pertinent information, such as basic brain histology, disease pathogenesis, and genetic profiles of victims. The paper will then discuss the available treatment options, from their annual costs and mechanisms of action to an evaluation of their cost-effectiveness. The information in this paper was collected through an online investigation of sources including research studies and medical journals. The treatments discussed in this thesis consist of six drugs: aducanumab, donepezil, rivastigmine, galantamine, memantine, and memantine-donepezil combination. Aducanumab is the only disease-modifying drug to receive FDA approval, but its efficacy is marred in controversy and it lacks cost-effectiveness. The remaining five drugs all have similar cost-effective values, but generic donepezil is an outlier with significantly better results. This paper’s findings indicate that generic donepezil is the most optimal treatment, but that further research should be conducted on aducanumab. Research also suggests that public health advocates must be vigorous in their attempts to make these drugs more affordable to the general population.

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