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Your search keyword '"Kline, Rachel"' showing total 2 results
Start Over Author "Kline, Rachel" Publication Type Electronic Resources
2 results on '"Kline, Rachel"'

1. Refining and applying comparative proteomics workflows to uncover novel regulators of neuronal stability between childhood and adult-onset degenerative diseases

Author

Kline, Rachel Ann, Wishart, Thomas, and Pennetta, Giuseppa

Subjects
neurodegenerative diseases, amyotrophic lateral sclerosis, ALS, CLN3, neurons, synapses, retinoid X- receptor
Abstract

Early structural, functional and molecular dysregulation in the synapse unites the majority of neurodegenerative conditions, including those without any current available therapeutic option. These similarities suggest that conserved pathways may promote a common neurodegenerative phenotypes, regardless of age of onset, aetiology (genetic or otherwise), or affected neuronal population. Identifying the molecular dysregulation linking synaptic vulnerability across multiple conditions may therefore uncover targetable regulatory elements conserved across the neurodegenerative spectrum irrespective of aetiological origin. Tandem mass tagging-based proteomic profiling of pre-symptomatic SMA (spinal muscular atrophy - a childhood MND), ALS type 8 (amyotrophic lateral sclerosis - a late adult onset MND), and CLN3 (a juvenile NCL) models through parameters of regional vulnerability and pathological gene "dose" identified 200 conserved candidates altered in a dose-dependent manner with respect to their distinct causative mutations. Predictive in silico analyses confirmed that these individual protein alterations interact hierarchically to mediate dysregulation in a broader cellular context, including changes in a number of metabolic pathways. In vivo genetic and pharmacological manipulation of the majority of conserved candidates, as well as the retinoid-X-receptor (RXR)-the strongest predicted upstream "master regulator" of identified conserved protein alterations-regulates degeneration across Drosophila models of both CLN3 and ALS type 8. Investigation within the synaptic proteomes of differentially vulnerable regions in post mortem brains reveals that these regulatory cascades are also activated in a regional-vulnerability-dependent manner in spontaneous ALS with predictive mechanistic regulation of lipid homeostasis. These results provide evidence for shared pathogenic mechanisms promoting a common degenerative signature that link otherwise unrelated degenerative diseases affecting every stage of the human lifecourse.

Published
2022
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2. The Proteome Signatures of Fibroblasts from Patients with Severe, Intermediate and Mild Spinal Muscular Atrophy Show Limited Overlap

Author

Brown, Sharon J., Kline, Rachel A., Synowsky, Silvia A., Shirran, Sally L., Holt, Ian, Sillence, Kelly A., Claus, Peter, Wirth, Brunhilde, Wishart, Thomas M., Fuller, Heidi R., Brown, Sharon J., Kline, Rachel A., Synowsky, Silvia A., Shirran, Sally L., Holt, Ian, Sillence, Kelly A., Claus, Peter, Wirth, Brunhilde, Wishart, Thomas M., and Fuller, Heidi R.

Abstract

Most research to characterise the molecular consequences of spinal muscular atrophy (SMA) has focused on SMA I. Here, proteomic profiling of skin fibroblasts from severe (SMA I), intermediate (SMA II), and mild (SMA III) patients, alongside age-matched controls, was conducted using SWATH mass spectrometry analysis. Differentially expressed proteomic profiles showed limited overlap across each SMA type, and variability was greatest within SMA II fibroblasts, which was not explained by SMN2 copy number. Despite limited proteomic overlap, enriched canonical pathways common to two of three SMA severities with at least one differentially expressed protein from the third included mTOR signalling, regulation of eIF2 and eIF4 signalling, and protein ubiquitination. Network expression clustering analysis identified protein profiles that may discriminate or correlate with SMA severity. From these clusters, the differential expression of PYGB (SMA I), RAB3B (SMA II), and IMP1 and STAT1 (SMA III) was verified by Western blot. All SMA fibroblasts were transfected with an SMN-enhanced construct, but only RAB3B expression in SMA II fibroblasts demonstrated an SMN-dependent response. The diverse proteomic profiles and pathways identified here pave the way for studies to determine their utility as biomarkers for patient stratification or monitoring treatment efficacy and for the identification of severity-specific treatments.

Published
2022

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