Thesis (Ph. D.)--Oregon State University, 2007. / Printout. Includes bibliographical references (leaves 127-134). Also available on the World Wide Web.

The Hippo pathway is a cell signaling pathway involved in organ size regulation and tumorigenesis in mammals. This pathway regulates the activity of Yes-associated protein (YAP), a transcriptional coactivator which binds to the transcription factor TEAD to promote expression of genes controlling growth and proliferation of tissues, as well as inhibition of apoptosis. The Hippo pathway has recently been implicated as a pathogenic mechanism in neurodegenerative disorders. Specifically, mammalian sterile 20 (Ste20)-like kinase 1 (MST1), a protein kinase in the Hippo pathway, has been found to promote neuronal death under conditions of oxidative stress. Moreover, homozygous deletion of MST1 in a mouse model of Amyotrophic Lateral Sclerosis (ALS) significantly delayed onset of neurodegenerative symptoms. We examined the expression levels of key Hippo pathway components in cortex, lumbar spinal cord, and gastrocnemius muscle samples of male and female G39A SOD1 mice using western blots. Our results revealed a significant increase in phosphorylated MST1 (pMST1) in lumbar spinal cord of presymptomatic transgenic animals, and found this increase to be sex and gene copy number dependent. These results suggest that the Hippo pathway is dysregulated in the SOD1 mouse model and that MST1 may play a critical role in pathogenesis and disease progression in ALS.

Amyotrophic lateral sclerosis is a relentlessly progressive and fatal neuromuscular disease with no effective biomarkers, treatments or cure. In the early stages of ALS, it can be difficult to provide a diagnosis as patients do not meet diagnostic criteria until they become symptomatic, a sign of neuron degeneration. Early detection is therefore crucial to provide access to therapeutics prior to significant neuron loss. Extracellular vesicles are an ideal source of biomarkers as they contain a mix of proteins and nucleic acids reflective of the physiological state and are released from all cell types. We identified valosin-containing protein, integrin-beta 1 and gelsolin as potential biomarkers for ALS14 through proteomic analysis of EVs isolated from cell lines carrying the ALS-associated VCP-R155H mutation. My results indicate that EVs may serve as a valuable source of protein biomarkers in diagnostic, prognostic and predictive applications.

Dominant mutations in profilin-1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by motor neuron loss, paralysis, and death from respiratory failure. Our lab recently demonstrated that PFN1 mutant proteins are destabilized—they unfold at milder conditions during thermal and chemical denaturation. Furthermore, we and others have shown that mutant PFN1 is more prone to misfold and aggregate. This misfolding alters PFN1’s protein-protein interactions, as demonstrated by an affinity purification-mass spectrometry screen. While ALS-associated mutants do not show loss of interaction, several have altered interactions with several formin family proteins, a group of proteins that interacts with profilins to regulate actin polymerization. These perturbations in profilin-formin interaction result in changes in actin metabolism, as shown by stress fiber formation in a HeLa model and neurite outgrowth in an iPSC-derived neuron model. Additionally, one mutant shows increased actin filament survival time in a microfluidic experiment, indicative of tighter binding in the actin-profilin-formin complex at the growing end of a filament. Misfolding and aggregation also puts additional stress on the cell’s proteostasis pathways. A cell culture model shows that misfolded Pfn1 is processed primarily by the proteasome, with modest contributions from autophagy. Together, this evidence provides additional support for two theories of Pfn1 ALS pathogenesis: disruptions in cytoskeletal function and proteostatic stress.

In Western countries the incidence of amyotrophic lateral sclerosis (ALS) is 1.89 per 100,000 per year and the prevalence is 5.2 per 100,000. The incidence of ALS is lower among African, Asian, and Hispanic ethnicities when compared to Caucasians. The mean age of onset for sporadic ALS is about 60 years and there is a slight male predominance (male to female ratio of 1.5 to 1). Approximately two thirds of patients with ALS have the spinal form of the disease with symptoms presenting in the extremities. Patients typically have evidence of both lower motor neuron degeneration (atrophy, weakness, and fasciculations) and upper motor neuron degeneration (spasticity, weakness, and hyperreflexia). Patients with limb onset ALS typically complain of focal muscle weakness and wasting. The symptoms may start either distally or proximally in the upper and/or lower limbs. Gradually spasticity develops in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS typically present with dysarthria and dysphagia for solid or liquids. Limb symptoms can develop simultaneously with bulbar onset. In the vast majority of patients, limb weakness will occur within 1-2 years of bulbar onset ALS symptoms. A case of bulbar and sporadic limb ALS in a 70-year-old veteran, presenting with right diaphragmatic paralysis and respiratory failure, is presented.

No description available.

The purpose of this thesis is to examine how rehabilitation interventions, specifically physiotherapy (PT), occupational therapy (OT), and speech and language pathology (SLP) or a combination of these interventions affect quality of life (QoL) in people with amyotrophic lateral sclerosis (ALS). The purpose of the first study (Chapter 2) was to synthesize qualitative research through a qualitative meta-synthesis on the potential of rehabilitation interventions to maintain and/or improve QoL from the perspective of people with ALS. The literature search for this study was conducted using the SPIDER strategy and five articles were included. Four themes emerged: 1) the concept of control; 2) adapting interventions to disease stage; 3) struggles with interventions; and 4) barriers between healthcare providers and patients. The evidence suggests that from the perspective of people with ALS, PT, OT, and SLP interventions, or a combination of these interventions have the potential to be beneficial in the management of people with ALS and to optimize QoL. The systematic review (Chapter 3) aimed to determine the effectiveness of rehabilitation interventions, in particular PT, OT and SLP interventions or a combination of these interventions, on QoL in people with ALS. The PICO search strategy was used and six studies were included: three RCTs, two cohort studies, and one cross-sectional study. A narrative synthesis of interventions was conducted as the included studies were not sufficiently similar thus data extracted were not adequate for conducting meta-analyses. Need to briefly discuss interventions, which outcomes you included and inconsistency in results across studies. Due to the limited evidence, it was difficult to determine the exact effects of the interventions from each rehabilitation field to affect QoL for people with ALS. The evidence suggests that more research is required; currently therapists need to rely on their clinical expertise, expert opinions, and theoretical models to select the most effective interventions to sustain or improve QoL in people with ALS. Future research needs to take into consideration the needs of people with ALS to evaluate the impact of rehabilitation interventions on QoL. / Thesis / Master of Science (MSc)

Thesis (M.S.)--West Virginia University, 2002. / Title from document title page. Document formatted into pages; contains ix, 67 p. : ill. Includes abstract. Includes bibliographical references (p. 63-67).

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Texas Health Science Center at Houston, School of Public Health, 1994. / Includes bibliographical references (leaves 163-169).