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1.  Age associated changes in gene expression in human brain and isolated neurons 
Neurobiology of aging  2012;34(4):1199-1209.
Previous studies have suggested that there are genes whose expression levels are associated with chronological age. However, which genes show consistent age association across studies, and which are specific to a given organism or tissue remains unresolved. Here, we re-assessed this question using two independently ascertained series of human brain samples from two anatomical regions, the frontal lobe of the cerebral cortex and cerebellum. Using microarrays to estimate gene expression, we found sixty associations between expression and chronological age that were statistically significant and were replicated in both series in at least one tissue. There were a greater number of significant associations in the frontal cortex compared to the cerebellum. We then repeated the analysis in a subset of samples using laser capture microdissection to isolate purkinje neurons from the cerebellum. We were able to replicate five gene associations from either frontal cortex or cerebellum in the Purkinje cell dataset, suggesting that there is a subset of genes have robust changes withs aging. Of these, the most consistent and strongest association was with expression of RHBDL3, a rhomboid protease family member. We confirmed several hits using an independent technique (qRT-PCR) and in an independent published sample series that used a different array platform. We also interrogated larger patterns of age related gene expression using weighted gene correlation network analysis (WGCNA). We found several modules that showed significant associations with chronological age and, of these, several that showed negative associations were enriched for genes encoding components of mitochondria. Overall, our results show that there is a distinct and reproducible gene signature for aging in the human brain.
PMCID: PMC3545059  PMID: 23177596
2.  Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia 
Alzheimer disease and associated disorders  2012;10.1097/WAD.0b013e318266fae5.
PMCID: PMC3511614  PMID: 22892647
frontotemporal lobar degeneration; frontotemporal dementia; mutation; TARDBP; TDP-43; C9ORF72
3.  UNC13A influences survival in Italian ALS patients: a population-based study 
Neurobiology of aging  2012;34(1):357.e1-357.e5.
The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to ALS, as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1,457 Italian control samples. Although rs12608932 was not associated to ALS susceptibility in our series (p=0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [IQR 2.2–6.4]; CC = 2.5 years [IQR 1.6–4.2]; p=0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p=0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an ~1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression.
PMCID: PMC3483408  PMID: 22921269
4.  Frontotemporal dementia with a C9ORF72 expansion in a Swedish family: clinical and neuropathological characteristics 
Background: In 2011 the C9ORF72 repeat expansion was identified as the most frequent genetic mutation underlying FTD and ALS. The main aim of this study was to investigate clinical characteristics in a large C9ORF72-positive FTD family, and to compare these with the neuropathological findings. Methods: The clinical records of 12 related FTD patients were thoroughly evaluated. The five neuropathologically examined cases were revised using additional TDP-43 immuno-stainings. Four cases were screened for the C9ORF72 expansion. Results: All 12 patients fulfilled the criteria for bvFTD. Restlessness and social neglect were often among the first reported symptoms. Psychotic symptoms were reported in 8 patients. Somatic complaints were seen in 7 cases. All the neuropathologically examined cases were TDP-43 positive. Conclusions: The phenotype of this C9ORF72 hexanucleotide expansion carrier family was bvFTD. The clinical symptom profile was strikingly homogenous. Psychotic symptoms and somatic complaints were observed in most of the cases.
PMCID: PMC3852567  PMID: 24319645
Genetics; FTD; longitudinal study; psychotic symptoms; TDP-43
5.  Prion-like domain mutations in hnRNPs cause multisystem proteinopathy and ALS 
Nature  2013;495(7442):467-473.
Algorithms designed to identify canonical yeast prions predict that ~250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here, we define pathogenic mutations in PrLDs of hnRNPA2/B1 and hnRNPA1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and a case of familial ALS. Wild-type hnRNPA2 and hnRNPA1 display an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Importantly, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant ‘steric zipper’ motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs must be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.
PMCID: PMC3756911  PMID: 23455423
6.  Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis 
Neurobiology of aging  2010;33(2):418-420.
Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated through the Ca2+-permeable AMPA-type of glutamate receptors and Ca2+ permeability is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no non-synonymous coding variants were observed but 24 polymorphisms were identified, 9 of which were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication set of 3,157 cases and 5,397 controls from 6 additional populations no association with susceptibility, age at onset or disease duration was observed. We conclude that polymorphisms in the GluR2 gene (GRIA2) are not a major contributory factor in the pathogenesis of ALS.
PMCID: PMC2949683  PMID: 20409611
Amyotrophic lateral sclerosis; excitotoxicity; GluR2; motor neuron
7.  Clinical Characteristics of C9ORF72-Linked Frontotemporal Lobar Degeneration 
The most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) has been linked to a hexanucleotide repeat expansion in the C9ORF72 gene. The frequency of the C9ORF72 expansion in Finland is among the highest in the world.
We assessed 73 Finnish patients with FTLD in order to examine the clinical characteristics associated with the expanded C9ORF72. Demographic and clinical features were evaluated. As a potential disease modifier, the apolipoprotein E (APOE) genotype was also assessed. Neuropathological analysis was available on 2 expansion carriers and 1 non-carrier.
The C9ORF72 expansion was present in 20 of 70 (29%) probands. Significant associations with the C9ORF72 expansion were observed for concomitant ALS and positive family history of dementia or ALS. Psychoses were detected in both carriers and non-carriers (21 vs. 10%, p = 0.25). The APOE ε4 allele did not cluster among expansion carriers. Numerous p62-positive neuronal inclusions were detected in the cerebellar cortex of the 2 expansion carriers.
In line with the suggested C9ORF72 core phenotype, we also detected a high frequency of neuropsychiatric symptoms; however, these symptoms seem not be specific to C9ORF72-associated FTLD. FTLD should be considered in cases of middle-age-onset psychosis.
PMCID: PMC3776392  PMID: 24052799
Association study; Clinical features; Frontotemporal dementia; Frontotemporal lobar degeneration; Genetics
9.  The Era of Genomic Epidemiology 
Neuroepidemiology  2009;33(3):276-279.
The recent revolution in genomics is already having a profound impact on the practice of epidemiology. The purpose of this commentary is to demonstrate how genomics and epidemiology will continue to rely heavily on each other, now and in the future, by illustrating a number of interaction points between these 2 disciplines: (1) the use of genomics to estimate disease heritability; (2) the impact of genomics on analytical study design; (3) how genome-wide data can be employed to effectively overcome residual population stratification arising from selection bias; (4) the importance of genomics as a tool in epidemiological investigation; (5) the importance of epidemiology in the collection of adequately phenotyped samples for genomics studies, and (6) for unraveling the clinical and therapeutic relevance of genetic variants once they are discovered.
PMCID: PMC2826447  PMID: 19696518
Genetics; Genomics; Epidemiology
10.  Road to the chromosome 9p-linked ALS/FTD locus 
PMCID: PMC3513280  PMID: 22399792
11.  Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72 
Brain  2012;135(3):784-793.
A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ∼40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis–frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis–frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6–7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7–2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ∼60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.
PMCID: PMC3286333  PMID: 22366794
amyotrophic lateral sclerosis; familial ALS, C9ORF72 gene; phenotype–genotype correlation
12.  Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72 
Brain  2012;135(3):751-764.
Intronic expansion of the GGGGCC hexanucleotide repeat within the C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial and sporadic cases. Initial reports indicate that this variant within the frontotemporal dementia/amyotrophic lateral sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The amyotrophic lateral sclerosis/motor neuron disease phenotype is not yet well characterized. We report the clinical and pathological phenotypes associated with pathogenic C9ORF72 mutations in a cohort of 563 cases from Northern England, including 63 with a family history of amyotrophic lateral sclerosis. One hundred and fifty-eight cases from the cohort (21 familial, 137 sporadic) were post-mortem brain and spinal cord donors. We screened DNA for the C9ORF72 mutation, reviewed clinical case histories and undertook pathological evaluation of brain and spinal cord. Control DNA samples (n = 361) from the same population were also screened. The C9ORF72 intronic expansion was present in 62 cases [11% of the cohort; 27/63 (43%) familial, 35/500 (7%) cases with sporadic amyotrophic lateral sclerosis/motor neuron disease]. Disease duration was significantly shorter in cases with C9ORF72-related amyotrophic lateral sclerosis (30.5 months) compared with non-C9ORF72 amyotrophic lateral sclerosis/motor neuron disease (36.3 months, P < 0.05). C9ORF72 cases included both limb and bulbar onset disease and all cases showed combined upper and lower motor neuron degeneration (amyotrophic lateral sclerosis). Thus, clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis associated with both familial and sporadic presentations. Dementia was present in the patient or a close family member in 22/62 cases with C9ORF72 mutation (35%) based on diagnoses established from retrospective clinical case note review that may underestimate significant cognitive changes in late disease. All the C9ORF72 mutation cases showed classical amyotrophic lateral sclerosis pathology with TDP-43 inclusions in spinal motor neurons. Neuronal cytoplasmic inclusions and glial inclusions positive for p62 immunostaining in non-motor regions were strongly over-represented in the C9ORF72 cases. Extra-motor pathology in the frontal cortex (P < 0.0005) and the hippocampal CA4 subfield neurons (P < 0.0005) discriminated C9ORF72 cases strongly from the rest of the cohort. Inclusions in CA4 neurons were not present in non-C9ORF72 cases, indicating that this pathology predicts mutation status.
PMCID: PMC3286332  PMID: 22366792
amyotrophic lateral sclerosis; C9ORF72; dementia; neurodegeneration
13.  Expanding the genetics of amyotrophic lateral sclerosis and frontotemporal dementia 
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. It is now recognized that ALS and frontotemporal lobar degeneration (FTLD) form a clinical spectrum of disease with overlapping clinical, pathological and genetic features. This past year, the genetic causes of ALS have expanded to include mutations in the genes OPTN, VCP, and UBQLN2, and the hexanucleotide repeat expansion in C9ORF72. The C9ORF72 repeat expansion solidifies the notion that ALS and FTLD are phenotypic variations of a disease spectrum with a common molecular etiology. Furthermore, the C9ORF72 expansion is the genetic cause of a substantial portion of apparently sporadic ALS and FTLD cases, showing that genetics plays a clear role in sporadic disease. Here we describe the progress made in the genetics of ALS and FTLD, including a detailed look at how new insights brought about by C9ORF72 have both broadened and unified current concepts in neurodegeneration.
PMCID: PMC3506944  PMID: 22835154
15.  Amyotrophic Lateral Sclerosis–Frontotemporal Lobar Dementia in 3 Families With p.Ala382Thr TARDBP Mutations 
Archives of neurology  2010;67(8):1002-1009.
TAR DNA-binding protein 43, encoded by the TARDBP gene, has been identified as the major pathological protein of frontotemporal lobar dementia (FTLD) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Subsequently, mutations in the TARDBP gene have been detected in 2% to 3% of patients with ALS (both familial and sporadic ALS). However, to our knowledge, there is only 1 description of 2 patients with FTLD and TARDBP gene mutations who later developed motor neuron disease.
To describe cognitive abnormalities in 3 Italian families with familial ALS and TARDBP gene mutations.
Design, Setting, and Participants
Genetic, neuropsychological, and neuroimaging analyses in 36 patients with familial non–superoxide dismutase 1 gene (SOD1) ALS and 280 healthy controls.
Main Outcome Measure
We identified 3 index cases of familial ALS carrying the p.Ala382Thr missense mutation of the TARDBP gene and with clinical, neuroimaging, and neuropsychological features of FTLD.
The p.Ala382Thr missense mutation of the TARDBP gene was absent in the 280 controls. It was present in all affected members of the 3 families for whom DNA was available. All affected members of the 3 families developed FTLD after the onset of ALS, confirmed by neuropsychological testing and hypometabolism in frontal associative areas assessed with fludeoxyglucose F 18 positron emission tomography and computed tomography.
Three apparently unrelated families with familial ALS carrying the p.Ala382Thr TARDBP missense mutation developed FTLD. In these families, FTLD co-segregates with ALS. Patients with ALS carrying TARDBP mutations may develop FTLD.
PMCID: PMC3535689  PMID: 20697052
16.  Mutational analysis of the VCP gene in Parkinson’s Disease 
Neurobiology of aging  2011;33(1):209.e1-209.e2.
Mutations in the valosin-containing protein gene (VCP) have been identified in neurological disorders (IBMPFD and ALS) and are thought to play a role in the clearance of abnormally folded proteins. Parkinsonism has been noted in kindreds with VCP mutations. Based on this, we hypothesized that mutations in VCP may also contribute to idiopathic PD. We screened the coding region of the VCP gene in a large cohort of 768 late onset PD cases (average age at onset = 70 years), both sporadic and with positive family history. We identified a number of rare single nucleotide changes, including a variant previously described to be pathogenic, but no clear disease-causing variants. We conclude that mutations in VCP are not a common cause for idiopathic PD.
PMCID: PMC3221929  PMID: 21920633
17.  The chromosome 9 ALS and FTD locus is probably derived from a single founder 
Neurobiology of Aging  2011;33(1):209.e3-209.e8.
We and others have recently reported an association between ALS and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data is that there is a single founder for this form of disease.
PMCID: PMC3312749  PMID: 21925771
Genetics; amyotrophic lateral sclerosis; frontotemporal dementia; Finland
18.  GroupICA dual regression analysis of resting state networks in a behavioral variant of frontotemporal dementia 
Functional MRI studies have revealed changes in default-mode and salience networks in neurodegenerative dementias, especially in Alzheimer's disease (AD). The purpose of this study was to analyze the whole brain cortex resting state networks (RSNs) in patients with behavioral variant frontotemporal dementia (bvFTD) by using resting state functional MRI (rfMRI). The group specific RSNs were identified by high model order independent component analysis (ICA) and a dual regression technique was used to detect between-group differences in the RSNs with p < 0.05 threshold corrected for multiple comparisons. A y-concatenation method was used to correct for multiple comparisons for multiple independent components, gray matter differences as well as the voxel level. We found increased connectivity in several networks within patients with bvFTD compared to the control group. The most prominent enhancement was seen in the right frontotemporal area and insula. A significant increase in functional connectivity was also detected in the left dorsal attention network (DAN), in anterior paracingulate—a default mode sub-network as well as in the anterior parts of the frontal pole. Notably the increased patterns of connectivity were seen in areas around atrophic regions. The present results demonstrate abnormal increased connectivity in several important brain networks including the DAN and default-mode network (DMN) in patients with bvFTD. These changes may be associated with decline in executive functions and attention as well as apathy, which are the major cognitive and neuropsychiatric defects in patients with frontotemporal dementia.
PMCID: PMC3752460  PMID: 23986673
default; resting state; functional MRI; dorsal attention network; frontotemporal dementia
20.  APOE and A-betaPP Gene Variation in Cortical and Cerebrovascular Amyloid-beta Pathology and Alzheimer’s Disease: A Population-Based Analysis 
Cortical and cerebrovascular amyloid-beta (A-beta) deposition is a hallmark of Alzheimer’s disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) epsilon4 is a major genetic modulator of A-beta deposition and AD risk. Variants of the amyloid-beta protein precursor (A-betaPP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and A-beta PP variants in cortical and cerebrovascular A-beta deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged ≥85 years (Vantaa85 + Study; n = 282). Our updated analysis of APOE showed strong associations of the epsilon4 allele with cortical (p = 4.91×10−17) and cerebrovascular (p = 9.87×10−11) A-beta deposition as well as with NIA-RI AD (p = 1.62×10−8). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the A-betaPP locus. In single SNP or haplotype analyses there were no statistically significant A-betaPP locus associations with cortical or cerebrovascular A-beta deposition or with NIA-RI AD. We sequenced the promoter of the A-betaPP gene in 40 subjects with very high A-beta deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular A-beta depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE epsilon4 variant. Promoter mutations or common allelic variation in the A-betaPP gene do not have a major contribution to cortical or cerebrovascular A-beta deposition, or very late-onset AD in this Finnish population based study.
PMCID: PMC3516850  PMID: 21654062
21.  Amyotrophic lateral sclerosis, physical exercise, trauma and sports: Results of a population-based pilot case-control study 
Our objective was to investigate exposure to physical exercise and trauma in patients with amyotrophic lateral sclerosis (ALS) compared to the general population. Previous studies in this area have yielded conflicting results. Using population-based ALS registries from Italy, the UK and Ireland, newly diagnosed patients with definite, probable or possible ALS were enrolled in a case-control study with two age- and sex-matched controls for each patient. Source, intensity and duration of physical activity and history of trauma were recorded. We here present the results of a pilot investigation. We studied 61 patients and 112 controls. Forty-one per cent of cases and 17.0% of controls (p = 0.001) had blue-collar occupations; 13.1% versus 3.6% reported strenuous physical activity at work (p = 0.05). Compared with controls, ALS patients had a longer exposure to work-related (10.7 vs. 7.3 years; p = 0.02) and sport-related physical exercise (9.6 vs. 5.2 years; p = 0.005). Three patients (0 controls) reported professional sports (p < 0.04). Traumatic events were similar. Blue collar occupation (OR 4.27; 95% CI 1.68–10.88) and duration of sport-related physical exercise (OR 1.03; 95% CI 1.00–1.05) were independent variables in multivariate analysis. We concluded that ALS is associated with physical exercise but not with traumatic events.
PMCID: PMC3513269  PMID: 20433412
22.  The epidemiology and treatment of ALS: Focus on the heterogeneity of the disease and critical appraisal of therapeutic trials 
Effective treatments for amyotrophic lateral sclerosis (ALS) have remained elusive. Only riluzole, a drug thought to affect glutamate metabolism, improves survival albeit to modest extent. Explanations for the negative results of therapeutic trials include a likely heterogeneity, both in disease susceptibility and pathogenic mechanisms, and faulty methodology of clinical trials. Further understanding of these factors will lead to improvements in patient stratification, and in the design of future clinical trials.
PMCID: PMC3513399  PMID: 20698807
23.  A patient carrying a homozygous p.A382T TARDBP missense mutation shows a syndrome including ALS, extrapyramidal symptoms and FTD 
Neurobiology of aging  2011;32(12):2327.e1-2327.e5.
We have recently published data showing that a founder mutation of the TARDBP gene (p.A382T) accounts for approximately one third of ALS cases on the Mediterranean island of Sardinia (Chiò et al, 2011). In that report, we identified 53 years-old man carrying a homozygous A382T missense mutation of the TARDBP gene with a complex neurological syndrome including ALS, parkinsonian features, motor and vocal tics, and frontotemporal dementia (FTD). Due to the uniqueness of this case, here we provide a detailed clinical description, as well as neurophysiological, neuropsychological and neuroimaging data for that case and his extended family.
PMCID: PMC3192246  PMID: 21803454
24.  No major progranulin genetic variability contribution to disease etiopathogenesis in an ALS Italian cohort 
Neurobiology of aging  2009;32(6):1157-1158.
To analyze the contribution of progranulin (PGRN) to the etiopathogenesis of amyotrophic lateral sclerosis (ALS), we performed a PGRN gene screening in 146 Italian patients (12 familial cases) and evaluated the association of two common variants with risk of developing ALS in 239 sporadic cases (SALS). Progranulin mRNA and protein levels were measured in peripheral blood mononuclear cells and serum of a subset of these patients and controls. PGRN sequence analysis revealed a heterozygous change (p.S120Y), previously observed in an independent sporadic ALS-FTD patient. Haplotype analysis showed a conserved PGRN region among these two subjects consistent with possible common ancestor allele. Two non-coding polymorphisms were not associated to increased risk to develop ALS; mRNA and serum levels were not significantly different between cases and controls. Overall, our data argue against the hypothesis of progranulin as a major risk factor for motor neuron dysfunction, at least in Italian population. The p.S120Y variant may characterize rare patients with SALS, although its pathogenetic mechanism remains to be elucidated.
PMCID: PMC3511779  PMID: 19632744
25.  The RNA-binding motif 45 (RBM45) protein accumulates in inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) patients 
Acta Neuropathologica  2012;124(5):717-732.
RNA-binding protein pathology now represents one of the best characterized pathologic features of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration patients with TDP-43 or FUS pathology (FTLD-TDP and FTLD-FUS). Using liquid chromatography tandem mass spectrometry, we identified altered levels of the RNA-binding motif 45 (RBM45) protein in the cerebrospinal fluid (CSF) of ALS patients. This protein contains sequence similarities to TAR DNA-binding protein 43 (TDP-43) and fused-in-sarcoma (FUS) that are contained in cytoplasmic inclusions of ALS and FTLD-TDP or FTLD-FUS patients. To further characterize RBM45, we first verified the presence of RBM45 in CSF and spinal cord tissue extracts of ALS patients by immunoblot. We next used immunohistochemistry to examine the subcellular distribution of RBM45 and observed in a punctate staining pattern within nuclei of neurons and glia in the brain and spinal cord. We also detected RBM45 cytoplasmic inclusions in 91 % of ALS, 100 % of FTLD-TDP and 75 % of Alzheimer’s disease (AD) cases. The most extensive RBM45 pathology was observed in patients that harbor the C9ORF72 hexanucleotide repeat expansion. These RBM45 inclusions were observed in spinal cord motor neurons, glia and neurons of the dentate gyrus. By confocal microscopy, RBM45 co-localizes with ubiquitin and TDP-43 in inclusion bodies. In neurons containing RBM45 cytoplasmic inclusions we often detected the protein in a punctate pattern within the nucleus that lacked either TDP-43 or ubiquitin. We identified RBM45 using a proteomic screen of CSF from ALS and control subjects for candidate biomarkers, and link this RNA-binding protein to inclusion pathology in ALS, FTLD-TDP and AD.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-012-1045-x) contains supplementary material, which is available to authorized users.
PMCID: PMC3472056  PMID: 22993125
Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; TDP-43; RNA-binding protein; RBM45; C9ORF72

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