Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression

Southwell, Amber L.; Smith, Stephen; Davis, Tessa R.; Caron, Nicholas S.; Villanueva, Erika B.; Xie, Yuanyun; Collins, Jennifer A.; Ye, Min Li; Sturrock, Aaron; Leavitt, Blair R.; Schrum, Adam G.; Hayden, Michael R.

doi:10.1038/srep12166

Cited by 94 publications

(110 citation statements)

References 33 publications

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“…Shortly afterwards, Southwell and colleagues reported mHTT quantification in CSF with immunoprecipitation and flow cytometry (IP-FCM) using a combination of MW1 and HDB4E10 antibodies, the latter recognizing a C-terminal binding site [84]. In a single cohort, overlapping with the Vancouver dataset from our work, they confirmed the presence of mHTT in mutation carriers but not controls and a tendency to rise with onset and clinical manifestations.…”

Section: Mutant Huntingtinsupporting

confidence: 70%

Cerebrospinal Fluid Biomarkers for Huntington’s Disease

Byrne¹,

Wild

2016

JHD

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Abstract. Cerebrospinal fluid (CSF) is enriched in brain-derived components and represents an accessible and appealing means of interrogating the CNS milieu to study neurodegenerative diseases and identify biomarkers to facilitate the development of novel therapeutics. Many such CSF biomarkers have been proposed for Huntington's disease (HD) but none has been validated for clinical trial use. Across many studies proposing dozens of biomarker candidates, there is a notable lack of statistical power, consistency, rigor and validation. Here we review proposed CSF biomarkers including neurotransmitters, transglutaminase activity, kynurenine pathway metabolites, oxidative stress markers, inflammatory markers, neuroendocrine markers, protein markers of neuronal death, proteomic approaches and mutant huntingtin protein itself. We reflect on the need for large-scale, standardized CSF collections with detailed phenotypic data to validate and qualify much-needed CSF biomarkers for clinical trial use in HD.

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Section: Mutant Huntingtinsupporting

confidence: 70%

Cerebrospinal Fluid Biomarkers for Huntington’s Disease

Byrne¹,

Wild

2016

JHD

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“…Although singleplex and multiplex immunoprecipitation detected by flow cytometry can be highly sensitive down to the femtomole to attomole analyte range (23–25), application of this technology to multiprotein complexes in signal transduction required the investigation of biostatistical analysis techniques. The present investigation involved the comparison of several statistical approaches using both empirical and computer-simulated experimentation to select an applicable statistical approach for PiSCES analysis.…”

Section: Discussionmentioning

confidence: 99%

Multiplex matrix network analysis of protein complexes in the human TCR signalosome

et al. 2016

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Multiprotein complexes transduce cellular signals through extensive interaction networks, but the ability to analyze these networks in cells from small clinical biopsies is limited. To address this, we applied an adaptable multiplex matrix system to physiologically relevant signaling protein complexes isolated from a cell line or from human patient samples. Focusing on the proximal T cell receptor (TCR) signalosome, we assessed 210 pairs of PiSCES (proteins in shared complexes detected by exposed surface epitopes). Upon stimulation of Jurkat cells with superantigen-loaded antigen-presenting cells, this system produced high-dimensional data that enabled visualization of network activity. A comprehensive analysis platform generated PiSCES biosignatures by applying unsupervised hierarchical clustering, principal component analysis, an adaptive nonparametric with empirical cutoff analysis, and weighted correlation network analysis. We generated PiSCES biosignatures from 4-mm skin punch biopsies from control patients or patients with the autoimmune skin disease alopecia areata. This analysis distinguished disease patients from the controls, detected enhanced basal TCR signaling in the autoimmune patients, and identified a potential signaling network signature that may be indicative of disease. Thus, generation of PiSCES biosignatures represents an approach that can provide information about the activity of protein signaling networks in samples including low-abundance primary cells from clinical biopsies.

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“…This ASO and others have undergone further development and improvement for human application to increase the specificity of the ASO to greater than 100-fold for mutant Htt allele over normal allele (Ostergaard et al, 2013). When evaluated in Hu97/18 mice exhibiting expression of both the mutant and wildtype Htt allele, specificity for the mutant allele was confirmed with specific reduction of mutant Htt without change to the normal mRNA or protein (Southwell et al, 2015) and demonstrated an extended duration of action from 16 to 32 weeks depending on the 2′ modification (Skotte et al, 2014). Whether these impressive qualities afford a therapeutic effect for modulating locomotor or cognitive deficits in HD mouse models remains to be determined.…”

Section: Application To Neurodegenerative Diseasesmentioning

confidence: 93%

Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

Schoch

Miller

2017

Neuron

234

254

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Multiple neurodegenerative diseases are characterized by single protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts resulting in reduced or modified protein expression. ASOs are ideal candidates for the treatment of neurodegenerative diseases given numerous advancements made to their chemical modifications and delivery methods. Successes achieved in both animal models and human clinical trials have proven ASOs both safe and effective. With proper considerations in mind regarding the human applicability of ASOs, we anticipate ongoing in vivo research and clinical trial development of ASOs for the treatment of neurodegenerative diseases.

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Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression

Cited by 94 publications

References 33 publications

Cerebrospinal Fluid Biomarkers for Huntington’s Disease

Cerebrospinal Fluid Biomarkers for Huntington’s Disease

Multiplex matrix network analysis of protein complexes in the human TCR signalosome

Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

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