Publications by authors named "Roshana Vander Wall"

Purpose: Remyelination therapies are advancing for multiple sclerosis, focusing on visual pathways and using visual evoked potentials (VEPs) for de/remyelination processes. While the cuprizone (CZ) model and VEPs are core tools in preclinical trials, many overlook the posterior visual pathway. This study aimed to assess functional and structural changes across the murine visual pathway during de/remyelination.

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Article Synopsis
  • * Recent research indicates that demyelination—the loss of protective myelin around nerve fibers—may contribute to the progression of glaucoma, with previous studies showing evidence in animal models and patients.
  • * This study is significant as it provides the first quantifiable evidence of reduced myelin proteins in the optic nerves of glaucoma patients, linking demyelination to nerve degeneration and increased glial activity, which supports theories about glaucoma's progression.
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Article Synopsis
  • - Glaucoma is a serious neurodegenerative disease that leads to the degeneration of retinal ganglion cells, potentially resulting in blindness, but the exact causes are still unclear.
  • - Previous research suggests that demyelination, or the loss of the protective myelin sheath around nerve axons, could be involved in glaucoma, although this hasn't been thoroughly documented in patients.
  • - This study utilized postmortem samples to confirm that glaucoma patients have significantly reduced myelin proteins and associated degenerative changes in the optic nerve, establishing a tangible link between demyelination and the progression of glaucoma.
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A prominent feature in many neurodegenerative diseases involves the spread of the pathology from the initial site of damage to anatomically and functionally connected regions of the central nervous system (CNS), referred to as transsynaptic degeneration (TSD). This review covers the possible mechanisms of both retrograde and anterograde TSD in various age-related neurodegenerative diseases, including synaptically and glial mediated changes contributing to TDS and their potential as therapeutic targets. This phenomenon is well documented in clinical and experimental studies spanning various neurodegenerative diseases and their respective models, with a significant emphasis on the visual pathway, to be explored herein.

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Neurodegenerative and demyelinating disease, such as multiple sclerosis (MS) are at the forefront of medical research and the discovery of new drugs and therapeutics. One phenomenon of degeneration seen in these diseases is transsynaptic degeneration (TSD), where damage from one axon spreads to the other axons that are connected to it synaptically. It has previously been found that demyelination occurs prior to neuronal loss in an experimental form of induced TSD.

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Neuropeptide Y (NPY), an endogenous peptide composed of 36 amino acids, has been investigated as a potential therapeutic agent for neurodegenerative diseases due to its neuroprotective attributes. This study investigated the neuroprotective effects of NPY in a mouse model of glaucoma characterized by elevated intraocular pressure (IOP) and progressive retinal ganglion cell degeneration. Elevated IOP in mice was induced through intracameral microbead injections, accompanied by intravitreal administration of NPY peptide.

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Neural regeneration and neuroprotection represent strategies for future management of neurodegenerative disorders such as Alzheimer's disease (AD) or glaucoma. However, the complex molecular mechanisms that are involved in neuroprotection are not clearly understood. A promising candidate that maintains neuroprotective signaling networks is neuroserpin (Serpini1), a serine protease inhibitor expressed in neurons which selectively inhibits extracellular tissue-type plasminogen activator (tPA)/plasmin and plays a neuroprotective role during ischemic brain injury.

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Although researched extensively the understanding regarding mechanisms underlying glaucoma pathogenesis remains limited. Further, the exact mechanism behind neuronal death remains elusive. The role of neuroinflammation in retinal ganglion cell (RGC) death has been prominently theorised.

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Myelination of axons in the central nervous system offers numerous advantages, including decreased energy expenditure for signal transmission and enhanced signal speed. The myelin sheaths surrounding an axon consist of a multi-layered membrane that is formed by oligodendrocytes, while specific glycoproteins and lipids play various roles in this formation process. As beneficial as myelin can be, its dysregulation and degeneration can prove detrimental.

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Glaucoma is a leading cause of permanent blindness worldwide and is characterized by neurodegeneration linked to progressive retinal ganglion cell (RGC) death, axonal damage, and neuroinflammation. Glutamate excitotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors plays a crucial role in glaucomatous RGC loss. Sphingosine 1-phosphate receptors (S1PRs) are important mediators of neurodegeneration and neuroinflammation in the brain and the retina.

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Glaucoma is a complex neurodegenerative disease characterized by optic nerve damage and apoptotic retinal ganglion cell (RGC) death, and is the leading cause of irreversible blindness worldwide. Among the sphingosine 1-phosphate receptors (S1PRs) family, S1PR1 is a highly expressed subtype in the central nervous system and has gained rapid attention as an important mediator of pathophysiological processes in the brain and the retina. Our recent study showed that mice treated orally with siponimod drug exerted neuroprotection via modulation of neuronal S1PR1 in experimental glaucoma.

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Autosomal recessive polycystic kidney disease (ARPKD) is an early onset genetic disorder characterized by numerous renal cysts resulting in end stage renal disease. Our study aimed to determine if metabolic reprogramming and tryptophan (Trp) metabolism via the kynurenine pathway (KP) is a critical dysregulated pathway in PKD. Using the Lewis polycystic kidney (LPK) rat model of PKD and Lewis controls, we profiled temporal trends for KP metabolites in plasma, urine, and kidney tissues from 6- and 12-week-old mixed sex animals using liquid and gas chromatography, minimum  = 5 per cohort.

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Sphingosine-1-phosphate receptor (S1PR) signaling regulates diverse pathophysiological processes in the central nervous system. The role of S1PR signaling in neurodegenerative conditions is still largely unidentified. Siponimod is a specific modulator of S1P1 and S1P5 receptors, an immunosuppressant drug for managing secondary progressive multiple sclerosis.

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Fingolimod (FTY720) is an oral drug approved by the Food and Drug Administration (FDA) for management of multiple sclerosis (MS) symptoms, which has also shown beneficial effects against Alzheimer's (AD) and Parkinson's (PD) diseases pathologies. Although an extensive effort has been made to identify mechanisms underpinning its therapeutic effects, much remains unknown. Here, we investigated Fingolimod induced proteome changes in the cerebellum (CB) and frontal cortex (FC) regions of the brain which are known to be severely affected in MS, using a tandem mass tag (TMT) isobaric labeling-based quantitative mass-spectrometric approach to investigate the mechanism of action of Fingolimod.

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Article Synopsis
  • There is a strong connection between eye diseases and brain diseases, where damage in one area can lead to degeneration in the other through a process called trans-synaptic degeneration (TSD).
  • TSD involves the deterioration of neural pathways and can significantly affect the clinical outcomes and functional abilities of individuals with neurodegenerative disorders.
  • The review discusses the neural connections and mechanisms involved in TSD within the visual system, emphasizing its importance for understanding disease progression and potential therapeutic targets.
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The noradrenaline transporter (NAT) transfers noradrenaline released into the synaptic cleft back into the presynaptic terminal, thus terminating neurotransmission. Although the distribution of NAT within the central nervous system has been well-characterized, less is known about its distribution elsewhere in the peripheral nervous system and in organs such as the skin. To address this in the present study, NAT expression was investigated using immunohistochemistry in the hind paw skin and more proximally in the sciatic nerve, dorsal root ganglia and spinal cord of five male Wistar rats.

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Glaucoma is characterized by the loss of retinal ganglion cells (RGC), and accordingly the preservation of RGCs and their axons has recently attracted significant attention to improve therapeutic outcomes in the disease. Here, we report that Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) undergoes activation in the RGCs, in animal model of glaucoma as well as in the human glaucoma tissues and that Shp2 dephosphorylates tropomyosin receptor kinase B (TrkB) receptor, leading to reduced BDNF/TrkB neuroprotective survival signaling. This was elucidated by specifically modulating Shp2 expression in the RGCs in vivo, using adeno-associated virus serotype 2 (AAV2) constructs.

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Glaucoma is a chronic disease that shares many similarities with other neurodegenerative disorders of the central nervous system. This study was designed to evaluate the association between glaucoma and other neurodegenerative disorders by investigating glaucoma-associated protein changes in the retina and vitreous humour. The multiplexed Tandem Mass Tag based proteomics (TMT-MS3) was carried out on retinal tissue and vitreous humour fluid collected from glaucoma patients and age-matched controls followed by functional pathway and protein network interaction analysis.

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Neuroserpin is a serine protease inhibitor that regulates the activity of plasmin and its activators in the neuronal tissues. This study provides novel evidence of regulatory effect of the neuroserpin on plasmin proteolytic activity in the retina in glaucoma. Human retinal and vitreous tissues from control and glaucoma subjects as well as retinas from experimental glaucoma rats were analysed to establish changes in plasmin and neuroserpin activity.

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Background: The DBA/2J mouse has been described as a model for congenital experimental glaucoma. It develops anterior segment anomalies with synechiae and pigment dispersion leading to raised intraocular pressure and glaucomatous damage. However, there are serious practical considerations when using this model in longitudinal studies.

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Accumulation of amyloid β (Aβ) and its aggregates in the ageing central nervous system is regarded synonymous to Alzheimer's disease (AD) pathology. Despite unquestionable advances in mechanistic and diagnostic aspects of the disease understanding, the primary cause of Aβ accumulation as well as its in vivo roles remains elusive; nonetheless, the majority of the efforts to address pathological mechanisms for therapeutic development are focused towards moderating Aβ accumulation in the brain. More recently, Aβ deposition has been identified in the eye and is linked with distinct age-related diseases including age-related macular degeneration, glaucoma as well as AD.

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The APP-PS1ΔE9 mouse model of Alzheimer's disease (AD) exhibits age dependent amyloid β (Aβ) plaque formation in their central nervous system due to high expression of mutated human APP and PSEN1 transgenes. Here we evaluated Aβ deposition and changes in soluble Aβ accumulation in the retinas of aged APP-PS1 mice using a combination of immunofluorescence, retinal flat mounts and western blotting techniques. Aβ accumulation in the retina has previously been shown to be associated with retinal ganglion cell apoptosis in animal models of glaucoma.

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TrkB is a high affinity receptor for the brain derived neurotrophic factor (BDNF) and its phosphorylation stimulates activation of several intracellular signalling pathways linked to cellular growth, differentiation and maintenance. Identification of various activators and inhibitors of the TrkB receptor and greater understanding their binding mechanisms is critical to elucidate the biochemical and pharmacological pathways and analyse various protein crystallization studies. The data presented here is related to the research article entitled "Brain Derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3β (GSK3β) signalling" [1].

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