Ubiquitin: a potential cerebrospinal fluid progression marker in Huntington's disease

Abstract

Multiple studies have shown that the ubiquitin-proteasome system is involved in Huntington's disease pathogenesis and understanding of this involvement may have therapeutic potential in humans. This is the first study on cerebrospinal fluid to confirm the involvement of the ubiquitin-proteasome system in Huntington's disease. Furthermore it is shown that ubiquitin increases with disease progression and CAG-age product score and therefore may have the potential as a Huntington's disease progression marker, also prior to motor onset.

Selected CSF biomarkers indicate no evidence of early neuroinflammation in Huntington disease

“…Participant characteristics are shown in table 1 and further described in earlier publications from our group. 12 , 14 Immunoglobulin G (IgG) index was not significantly different in the 3 groups ( p = 0.224) and the distribution of individuals who had an IgG index above normal (>0.67) did not differ in the 3 groups ( p = 0.294) either. CSF oligoclonal bands were detected in 3 gene-expansion negative controls, in 3 manifest HD gene-expansion carriers, and in 9 premanifest gene-expansion carriers.…”

“…Participants’ recruitment, exclusion and inclusion criteria, and investigation program is reported elsewhere. 12 Participants were classified according to the Unified Huntington’s Disease Rating Scale (UHDRS) total motor score (TMS) 13 with a UHDRS-TMS of >5 defined as motor manifest HD gene-expansion carriers. If the score was ≤5, indicating no substantial motor signs, they were classified as premanifest HD gene-expansion carriers .…”

“…CSF samples were obtained by lumbar puncture and processed as previously described. 12 Blood samples were drawn for corresponding blood biochemistry including leukocyte count and C-reactive protein (CRP) to control for possible infections. The following ELISAs were used to measure CSF biomarkers: C-X-C motif chemokine 13 (CXCL13), Quantikine ELISA Kit (R&D Systems, Minneapolis, MN); matrix metalloproteinase-9 (MMP9), Quantikine ELISA Kit; total nitric oxide and nitrite/nitrate (NO x ) assay; human osteopontin (OPN) and human chitinase 3-like 1 protein (CHI3L1), Quantikine ELISA Kit; neurofilament light polypeptide (NFL), ELISA (UmanDiagnostics, Umeå, Sweden); myelin basic protein (MBP) ELISA (Beckman Coulter, Sharon Hill, PA); TCC ELISA Kit (Hycult Biotech, Uden, Netherlands); and microtubule-associated protein tau (total) (Tau) human ELISA Kit (Life Technologies, Nærum, Denmark).…”

Cerebrospinal Fluid Biomarkers for Huntington’s Disease

“…After age-adjustment and Bonferroni correction, only ubiquitin remained significantly higher in manifest HD patients, with a trend in preHD compared to controls. The correlation between ubiquitin and CAG-age product (CAP) and other clinical measures was statistically significant [81]. Ubiquitin is added post-transcriptionally to flag proteins for degradation by the ubitiquitin-proteaseome system (UPS), and its elevation in CSF may reflect the gradual accumulation of unwanted proteins, perhaps including mHTT, in cells of the CNS.…”

Advances in neurological research and practice

“…Advances in neurology occur across a broad front including neuro‐oncology, trauma, neuro‐otology and neurodevelopment. These areas also overlap with other specialist areas within the neurosciences.…”