Profiling of ubiquitination pathway genes in peripheral cells from patients with frontotemporal dementia due to C9ORF72 and GRN mutations

We analysed the expression levels of 84 key genes involved in the regulated degradation of cellular protein by the ubiquitin-proteasome system in peripheral cells from patients with frontotemporal dementia (FTD) due to C9ORF72 and GRN mutations, as compared with sporadic FTD and age-matched controls. A SABiosciences PCR array was used to investigate the transcription profile in a discovery population consisting of six patients each in C9ORF72, GRN, sporadic FTD and age-matched control groups. A generalized down-regulation of gene expression compared with controls was observed in C9ORF72 expansion carriers and sporadic FTD patients. In particular, in both groups, four genes, UBE2I, UBE2Q1, UBE2E1 and UBE2N, were down-regulated at a statistically significant (p < 0.05) level. All of them encode for members of the E2 ubiquitin-conjugating enzyme family. In GRN mutation carriers, no statistically significant deregulation of ubiquitination pathway genes was observed, except for the UBE2Z gene, which displays E2 ubiquitin conjugating enzyme activity, and was found to be statistically significant up-regulated (p = 0.006). These preliminary results suggest that the proteasomal degradation pathway plays a role in the pathogenesis of FTD associated with TDP-43 pathology, although different proteins are altered in carriers of GRN mutations as compared with carriers of the C9ORF72 expansion

The novel GRN g.1159-1160delTG mutation is associated with behavioral variant frontotemporal dementia

Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration and are associated with a wide phenotypic heterogeneity. Here, we describe two probands with behavioral variant frontotemporal dementia with a novel mutation in this gene (1159-1160delTG). Both had a positive family history for dementia and showed atypical features at imaging. Their progranulin plasma levels were undetectable, and the mutation was not present in cDNA, suggesting haploinsufficiency. Progranulin levels were low even in asymptomatic carriers of the variant. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers

Plasma Screening for Progranulin Mutations in Patients with Progressive Supranuclear Palsy and Corticobasal Syndromes

Progranulin gene (GRN) mutations are characterized by heterogeneous presentations. Corticobasal syndrome (CBS) is often associated with GRN mutations, whereas association with progressive supranuclear palsy syndrome (PSPS) is rare. Plasma progranulin levels were evaluated in 34 patients, including 19 with PSPS, 12 with CBS, and 3 with mixed signs, with the purpose to screen for the presence of causal mutations, associated with low levels. We found undetectable levels in a patient with CBS. Sequencing confirmed the presence of the Thr272fs deletion. Progranulin mutation screening is suggested in cases of CBS, even in the absence of positive family history for dementia and/or movement disorders

Circulating miRNAs as potential biomarkers in Alzheimer&apos;s disease

Several micro(mi)RNA are deregulated in brain, cerebrospinal fluid (CSF), and serum/plasma from patients with Alzheimer's disease (AD). The aim of the study was to profile circulating miRNAs in serum as non-invasive biomarkers for AD, correlating them with those identified in CSF, the biological fluid which better reflects biochemical changes occurring during pathological processes in the brain and may provide a robust indicator of AD-related disease pathogenesis thanks to the evidence of low amyloid and high levels of tau and hyperphosphorylated tau. Using a two-step analysis (array and validation through real-time PCR), a down-regulation (mean fold change \ub1 SEM) of miR-125b (0.415 \ub1 0.11 versus 1.381 \ub1 0.36, p = 0.009), miR-23a (0.111 \ub1 0.03 versus 0.732 \ub1 0.14, p < 0.001), and miR-26b (0.414 \ub1 0.11 versus 1.353 \ub1 0.39, p < 0.01), out of 84 tested, was shown in serum from 22 AD patients compared with 18 non-inflammatory and 8 inflammatory neurological controls (NINDCs and INDCs) and 10 patients with frontotemporal dementia. Significant down-regulation of miR-125b and miR-26b was also confirmed in CSF from AD patients versus NINDCs (miR-125b: 0.089 \ub1 0.03 versus 0.230 \ub1 0.08, p < 0.001; miR-26b: 0.217 \ub1 0.06 versus 1.255 \ub1 0.29, p < 0.001, mean fold change \ub1 SEM, respectively), whereas data were not replicated for miR-23a. In serum, miR-125b had an AUC of 0.82 to distinguish AD from NINDCs (95% CI: 0.65-0.98, p = 0.005). In conclusion, we demonstrated that cell-free miR-125b serum levels are decreased in serum from patients with AD as compared with NINDC and distinguish between AD and NINDCs with an accuracy of 82%. Supplementary Figure 1. A) Array miRNA list; B) Heat map. Data are expressed as fold change (fold difference) in Alzheimer's disease patients versus controls and normalized on cel-miR-39. Each square represents a single miRNA. Green indicates down-regulation and red indicates upregulation

Profiling of specific gene expression pathways in peripheral cells from prodromal Alzheimer&apos;s disease patients

Herein, we performed a gene expression profiling in a cohort of 10 mild cognitive impairment (MCI), subdivided, according to the analysis of cerebrospinal fluid biomarkers, in prodromal Alzheimer's disease (AD) and non-AD MCI, as compared with 27 AD patients and 24 controls, in order to detect early gene expression alterations. We observed a significant upregulation of insulin (INS) and INS Receptor (INSR) expression levels in AD both prodromal and fully symptomatic, as compared with controls, but not in MCI subjects. Our results suggest an early dysregulation of INS and INSR in AD pathogenesis and pave the way to a possible utility of these transcripts as peripheral biomarkers

Incomplete penetrance of the C9ORF72 hexanucleotide repeat expansions : Frequency in a cohort of geriatric non-demented subjects

We genotyped for the C9ORF72 hexanucleotide repeat expansion a population of 156 non-demented elderly subjects, recruited in a geriatric unit as control group for association studies in patients with Alzheimer's disease (AD), and found two carriers (1.2%). The first was referred for subjective memory complaints, at age 81. He was followed up until age 84 and did not develop dementia. The second was an 80-year old volunteer (spouse and caregiver of a patient with AD), non-demented at time of recruitment. We have not had information on her condition since that time. These results suggest that the penetrance of the mutation is definitely incomplete. \ua9 2014-IOS Press and the authors

Non Fluent Variant of Primary Progressive Aphasia Due to the Novel GRN g.9543delA(IVS3-2delA) Mutation

Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration syndromes and are associated with a wide phenotypic heterogeneity. The majority of genetic defects in GRN consists of loss-of-function mutations, causing haploinsufficiency, and is associated with extremely low plasma progranulin levels. Herein, we describe a patient who developed language dysfunctions and memory disturbances at 63 years of age. Considering the early onset and the positive family history (sister aged 50 with non-fluent/agrammatic variant of primary progressive aphasia, father with behavioral disturbances in his sixties), a genetic analysis was carried out, showing the presence of a novel mutation [g.9543delA (IVS3-2delA)] in a predicted splicing site of GRN. Her progranulin plasma levels were under the reference threshold, as in her sister, thus supporting the causative role of the new variant. The same genetic mutation was confirmed by sequencing in her sister. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers

Inflammatory molecules in Frontotemporal Dementia : Cerebrospinal fluid signature of progranulin mutation carriers

Mutations in progranulin gene (. GRN) are one of the major causes of autosomal dominant Frontotemporal Lobar Degeneration (FTLD). Progranulin displays anti-inflammatory properties and is likely a ligand of Tumor Necrosis Factor (TNF) receptor 2, expressed on microglia. A few cytokines and chemokines are altered in cerebrospinal fluid (CSF) from patients with sporadic FTLD, whereas no information is available in familial cases. We evaluated, through BioPlex, levels of 27 inflammatory molecules, including cytokines, chemokines, and related receptors, in CSF and matched serum, from FTLD patients carrying GRN mutations as compared with sporadic FTLD with no GRN mutations and controls. Mean. \ub1. SD Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly increased in CSF from sporadic FTLD patients as compared with controls (334.27\ub1151.5 versus 159.7\ub149. pg/ml; P 640.05). In GRN mutation carriers versus controls, CSF levels of MCP-1 were unchanged, whereas Interferon-\u3b3-inducible protein-10 (IP-10) levels were increased (809.17. \ub1240.0 versus 436.61\ub1202.5. pg/ml; P=0.012). In the same group, TNF\u3b1 and Interleukin (IL)-15 levels were decreased (3.18. \ub11.41 versus 35.68\ub130.5pg/ml; P=0.013 and 9.34\ub15.54 versus 19.15\ub110.03pg/ml; P= 0.023, respectively). Conversely, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in patients, with or without mutations, as compared with controls (4.63\ub13.30 and 2.58\ub120 versus 87.57\ub170. pg/ml, respectively; P<0.05). Moreover, IP-10, IL-15 and RANTES CSF levels were not influenced by age, whereas MCP-1 levels increased with age (\u3c1=0.48; P=0.007). In conclusion, inflammatory de-regulation was observed in both sporadic FTLD and GRN carriers compared to controls, with a specific inflammatory profile for the latter group

C9ORF72 repeat expansion not detected in patients with multiple sclerosis

A hexanucleotide repeat expansion in the chromosome 9 Open Reading Frame 72 gene (C9ORF72) has recently been reported to be cause of familial amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Nevertheless, in the last few years this mutation has been found to be associated with heterogeneous phenotypes, including multiple sclerosis (MS) in concurrence with amyotrophic lateral sclerosis. In this study, we sought to evaluate the presence of the C9ORF72 repeat expansion in a cohort consisting of 314 patients with MS and 222 control subjects. No pathogenic expansion was found in MS and control populations, suggesting that C9ORF72 does not play a major role in MS pathogenesis. \ua9 2014 Elsevier Inc