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

Abstract

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

Prodynorphin and Proenkephalin in Cerebrospinal Fluid of Sporadic Creutzfeldt–Jakob Disease

“…However, apart from sCJD patients, decreased or a trend towards decreased CSF PENK levels were also previously reported in HD, AD, FTD and DLB, suggesting a common pathogenetic pathway in most proteinopathies [8,10]. Further study on larger patient cohorts will be needed to fully elucidate the precise role of brain opioid peptides in neurodegenerative diseases.…”

“…Endogenous opioids are a group of peptides that act on opioids receptors and that derive from proteolytic cleavage of three main precursors: proenkephalin (PENK), prodynorphin (PDYN) and pro-opiomelanocortin [7]. Altered levels of CSF PDYN and/or PENK-derived peptides have been reported in Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and Huntington's disease (HD) [8][9][10][11][12].…”

“…Initial evidence from these studies suggested that decreased CSF PDYN and PENK levels may reflect an impairment and/or neurodegeneration of the striatal medium spiny projection neurons (MSNs), which produce both peptides under dopaminergic signaling [9,10]. Moreover, dysfunctions in the PDYN pathway appear to be involved in developing behavioral and sleep disorders in neurodegenerative disease [12].…”

Cerebrospinal fluid amyloid beta and glial fibrillary acidic protein concentrations in Huntington’s disease

“…APP is a transmembrane protein with multiple physiological functions, including regulating brain iron homeostasis [53], and it is cleaved by beta- and gamma-secretase to form Aβ peptides [54, 55]. Our previous finding of decreased CSF transthyretin in HD patients [56] has also been reported in AD, where it possibly contributes to the failure of cerebral amyloid clearance [57]. This might allude to similarly decreased Aβ42 levels in HD, as noted in several other neurodegenerative disorders, most notably in AD [24–29].…”

Taming the Huntington’s Disease Proteome: What Have We Learned?

“…A 2011 study by Chen and colleagues showed increased levels of prothrombin, apolipoprotein A-IV (APOA4), and haptoglobin in CSF from a small group of control versus HD patients ( Table 3 ) [ 61 ]. Recently, a study using a larger cohort of patients reported changes in proenkephalin (PENK) and transthyretin between manifest and premanifest HD carriers which was confirmed in a second cohort, as well as numerous proteins changed between controls and HD carriers [ 62 ]. Interestingly, all three studies found increased APOA4 ( Table 3 ).…”