We identified a subset of genes involved in chromatin remodeling whose mRNA expression changes in differentiating mouse erythroleukemia (MEL) cells. We furthermore tested their mRNA expression patterns in normal and malignant CD34+ bone marrow cells. SMARCA5, imitation switch gene homologue, was rapidly silenced during in vitro erythroid differentiation of MEL cells whereas it was up-regulated in CD34 + hematopoietic progenitors of acute myeloid leukemia (AML) patients. Moreover, SMARCA5 mRNA levels decreased in AML CD34+ progenitors after the patients achieved complete hematologic remission. We detected high levels of SMARCA5 mRNA in murine bone marrow and spleen and monitored its expression in these hematopoietic tissues during accelerated hematopoiesis following hemolytic anemia induced by phenylhydrazine. SMARCA5 expression levels decreased after the onset of accelerated erythropoiesis. Our data suggest that both in vitro and in vivo induction of differentiation is followed by down-regulation of SMARCA5 expression. In CD34 + AML progenitors over-expression of SMARCA5 may thus dysregulate the genetic program required for normal differentiation. Leukemia (2000) 14, 1247-1252.

Cerebrospinal fluid (CSF) total prion protein (t-PrP) is decreased in sporadic Creutzfeldt-Jakob disease (sCJD). However, data on the comparative signatures of t-PrP across the spectrum of prion diseases, longitudinal changes during disease progression, and levels in pre-clinical cases are scarce. T-PrP was quantified in neurological diseases (ND, n = 147) and in prion diseases from different aetiologies including sporadic (sCJD, n = 193), iatrogenic (iCJD, n = 12) and genetic (n = 209) forms. T-PrP was also measured in serial lumbar punctures obtained from sCJD cases at different symptomatic disease stages, and in asymptomatic prion protein gene (PRNP) mutation carriers. Compared to ND, t-PrP concentrations were significantly decreased in sCJD, iCJD and in genetic prion diseases associated with the three most common mutations E200K, V210I (associated with genetic CJD) and D178N-129M (associated with fatal familial insomnia). In contrast, t-PrP concentrations in P102L mutants (associated with the Gerstmann-Sträussler-Scheinker syndrome) remained unaltered. In serial lumbar punctures obtained at different disease stages of sCJD patients, t-PrP concentrations inversely correlated with disease progression. Decreased mean t-PrP values were detected in asymptomatic D178-129M mutant carriers, but not in E200K and P102L carriers. The presence of low CSF t-PrP is common to all types of prion diseases regardless of their aetiology albeit with mutation-specific exceptions in a minority of genetic cases. In some genetic prion disease, decreased levels are already detected at pre-clinical stages and diminish in parallel with disease progression. Our data indicate that CSF t-PrP concentrations may have a role as a pre-clinical or early symptomatic diagnostic biomarker in prion diseases as well as in the evaluation of therapeutic interventions.

Background and ObjectivesFor early diagnosis and disease monitoring of neurodegenerative diseases (NDs), reliable blood biomarkers are needed. Elevated levels of neurofilament light chain protein (NfL), an axonal damage marker, have been described across different NDs, with highest values in prion diseases and amyotrophic lateral sclerosis (ALS). Synaptic degeneration is a common early feature in most NDs and seems to precede neuronal degeneration in prion disease. However, synaptic markers in blood are still missing. Here, we investigated whether the brain-specific protein β-synuclein might be a suitable blood biomarker for early diagnosis and evaluation of synaptic integrity in prion disease.MethodsWe analyzed blood β-synuclein with a newly established digital ELISA and NfL with a single-molecule array in samples obtained from human participants and prion and ALS animal models. Furthermore, β-synuclein was investigated in brain tissue of individuals with Creutzfeldt-Jakob disease (CJD) and controls.ResultsWe investigated 308 patients, including 129 cases with prion disease, 8 presymptomatic PRNP variation carriers, 60 with ALS, 68 with other ND, and 43 control patients. In CJD symptomatic cases, β-synuclein and NfL were markedly increased compared to all other diagnostic groups (p < 0.001). In the large majority of presymptomatic PRNP variation carriers, β-synuclein and NfL levels were within normal ranges. In prion disease animal models, β-synuclein and NfL displayed normal levels in the presymptomatic phase with a sudden elevation at disease onset and a plateau in the symptomatic phase. In contrast to NfL, β-synuclein was not elevated in either symptomatic patients with ALS or an ALS animal model. In the discrimination between prion disease and all other groups, β-synuclein (area under the curve 0.97, 95% CI 0.94–0.99, p < 0.001) was superior to NfL (area under the curve 0.91, 95% CI 0.88–0.94, p < 0.001). In addition, brain tissue β-synuclein showed significantly reduced levels in patients with CJD compared to control patients (p < 0.001).DiscussionBlood β-synuclein was significantly elevated in patients with CJD, reflecting ongoing synaptic damage, and showed good discriminative characteristics. We therefore propose it as a candidate blood marker for early diagnosis and monitoring of synaptic integrity in prion disease.Classification of EvidenceThis study provides Class III evidence that serum β-synuclein concentration accurately distinguishes patients with symptomatic CJD from controls.