Neuropeptide Y (<scp>NPY</scp>) in cerebrospinal fluid from patients with Huntington's Disease: increased <scp>NPY</scp> levels and differential degradation of the <scp>NPY</scp><sub>1–30</sub> fragment

Wagner, Leona; Björkqvist, Maria; Lundh, Sofia; Wolf, Reinhard; Börgel, Arne; Schlenzig, Dagmar; Ludwig, Hans-Henning; Rahfeld, Jens‐Ulrich; Leavitt, Blair R.; Demuth, Hans‐Ulrich; Petersén, Åsa; Hörsten, Stephan von

doi:10.1111/jnc.13624

Cited by 18 publications

(7 citation statements)

References 96 publications

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“…MERGL levels seemed to be affected by antipsychotics in the former study, but we could not find differing levels of PENK in the participants using antipsychotics. Contrary from the GABA‐ and enkephalinergic MSNs, neuropeptide Y (NPY)‐containing interneurons are spared in HD and higher levels of NPY have been reported in CSF of HD patients 23 . The authors suggested that a ratio between NPY and dynorphin‐A or enkephalin peptides could serve as a biomarker for HD onset or disease progression.…”

Section: Discussionmentioning

confidence: 99%

Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease

et al. 2020

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Objective Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies. Methods We conducted an unbiased mass‐spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 pre‐manifest (preHD), and 38 controls. A biologically plausible and significant possible biomarker was validated in samples from a separate cohort of patients and controls consisting of 23 ManHD patients and 23 controls. Results In ManHD compared to preHD, 10 proteins were downregulated and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin were closely linked to HD symptom severity, whereas levels of 15 upregulated proteins were associated with symptom severity. The decreased PENK levels were replicated in the separate cohort where absolute quantitation was performed. Conclusions We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 99%

Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease

et al. 2020

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“…Another possibility is that some large hNSCs could have evolved into NPY interneurons. Interestingly, in HD, MSNs expressing NPY are spared and their numbers are even upregulated in HD patients (Wagner et al, 2016). Based on passive and active membrane properties, some cells also differentiated into large cholinergic interneurons.…”

Section: Ultrastructural Evidence That Hnscs Establish Synaptic Contamentioning

confidence: 99%

Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum

Thompson

Holley

Reidling

et al. 2021

Preprint

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Huntington’s disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that hNSCs transplanted into the striatum of HD mouse models differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here we show that 8-month implantation of hNSCs into the striatum of zQ175 HD mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) and reduces mutant Huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry and electron microscopy demonstrates that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells. Remarkably, hNSCs receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

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“…Fragment N‐224 was significantly increased in AD patients, and increase of its abundance was related to a decrease in cognitive performance over time . In a similar way, the cleaved forms of neuropeptide Y have been studied as markers for Huntington's disease . The use of peptidomic approaches is rapidly expanding, and other body fluids on top of those previously mentioned, such as saliva and sweat, are also being tested as sources of proteolytic biomarker fragments …”

Section: Discovery Of Protease Substratesmentioning

confidence: 99%

Degradomics in Biomarker Discovery

Grozdanić

Vidmar

Vizovišek

et al. 2019

Proteomics Clinical Apps

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The upregulation of protease expression and proteolytic activity is implicated in numerous pathological conditions such as neurodegeneration, cancer, cardiovascular and autoimmune diseases, and bone degeneration. During disease progression, various proteases form characteristic patterns of cleaved proteins and peptides, which can affect disease severity and course of progression. It has been shown that qualitative and quantitative monitoring of cleaved protease substrates can provide relevant prognostic, diagnostic, and therapeutic information. As proteolytic fragments and peptides generated in the affected tissue are commonly translocated to blood, urine, and other proximal fluids, their possible application as biomarkers is the subject of ongoing research. The field of degradomics has been established to enable the global identification of proteolytic events on the organism level, utilizing proteomic approaches and sample preparation techniques that facilitate the detection of proteolytic processing of protease substrates in complex biological samples. In this review, some of the latest developments in degradomic methodologies used for the identification and validation of biologically relevant proteolytic events and their application in the search for clinically relevant biomarker candidates are presented. The current state of degradomics in clinics is discussed and the future perspectives of the field are outlined.

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Neuropeptide Y (NPY) in cerebrospinal fluid from patients with Huntington's Disease: increased NPY levels and differential degradation of the NPY_1–30 fragment

Cited by 18 publications

References 96 publications

Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease

Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease

Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum

Degradomics in Biomarker Discovery

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Neuropeptide Y (NPY) in cerebrospinal fluid from patients with Huntington's Disease: increased NPY levels and differential degradation of the NPY1–30 fragment

Cited by 18 publications

References 96 publications

Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease

Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease

Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum

Degradomics in Biomarker Discovery

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Product

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Neuropeptide Y (NPY) in cerebrospinal fluid from patients with Huntington's Disease: increased NPY levels and differential degradation of the NPY_1–30 fragment