Kathrin Müller

Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

Systemic dysregulation of TDP-43 binding microRNAs in amyotrophic lateral sclerosis

BackgroundA pathological hallmark of most amyotrophic lateral sclerosis (ALS) cases are intracellular aggregates of the protein TDP-43. The pathophysiological relevance of TDP-43 is underlined by familial ALS cases caused by TDP-43 mutations. TDP-43 is involved in processing of both coding RNAs and microRNAs, which are key epigenetic regulators of transcriptome plasticity and suspected to contribute to neurological diseases. We therefore asked whether the TDP-43 binding microRNAs recently identified in cell lines are also dysregulated in ALS patients. We compared their abundance in cerebrospinal fluid (CSF), serum and immortalized lymphoblast cell lines (LCLs) derived from ALS patients and healthy controls.ResultsWe found that expression levels of 5 out of 9 TDP-43 binding microRNAs were altered in the CSF and serum of sporadic ALS cases. The differentially regulated serum microRNAs together with a poor correlation between CSF and serum levels indicate a systemic dysregulation of microRNA abundance independent from the CSF compartment, in line with the ubiquitous expression of TDP-43. The most strongly regulated microRNAs could be confirmed in LCLs from genetically defined ALS patients. While dysregulation of miR-143-5p/3p seems to be a common feature of ALS pathology, downregulation of miR-132-5p/3p and miR-574-5p/3p was evident in sporadic, TARDBP, FUS and C9ORF72, but not SOD1 mutant patients. This parallels the TDP-43 pathology found in most ALS cases, but usually not in patients with SOD1 mutation.ConclusionsWe thus report a systemic and genotype-dependent dysregulation of TDP-43 binding microRNAs in human biomaterial that might reflect an easily accessible biological measure of TDP-43 dysfunction. Furthermore we suggest an independent regulation of TDP-43 binding microRNAs in the serum and CSF compartment as well as a generally low transition of microRNAs across the blood-cerebrospinal fluid barrier.

Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis.

Neurofilaments are elevated in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients. However, timing of this increase is unknown. To characterize the premanifest disease phase, we performed a cross‐sectional study on asymptomatic (n = 12) and symptomatic (n = 64) ALS mutation carriers and family controls (n = 19). Neurofilaments NF‐L (neurofilament–light chain) and pNF‐H (phosphorylated neurofilament–heavy chain) are normal before symptom onset and increased by at least an order of magnitude at early symptom onset in CSF (pNF‐H) or serum and CSF (NF‐L). Thus, blood and CSF neurofilament levels are linked to the symptomatic phase of ALS and might serve as objective markers of structural damage to the nervous system. ANN NEUROL 2016;79:152–158

Neurofilaments levels as biomarkers in asymptomatic and symptomatic familial ALS

Neurofilaments are elevated in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients. However, timing of this increase is unknown. To characterize the premanifest disease phase, we performed a cross‐sectional study on asymptomatic (n = 12) and symptomatic (n = 64) ALS mutation carriers and family controls (n = 19). Neurofilaments NF‐L (neurofilament–light chain) and pNF‐H (phosphorylated neurofilament–heavy chain) are normal before symptom onset and increased by at least an order of magnitude at early symptom onset in CSF (pNF‐H) or serum and CSF (NF‐L). Thus, blood and CSF neurofilament levels are linked to the symptomatic phase of ALS and might serve as objective markers of structural damage to the nervous system. ANN NEUROL 2016;79:152–158

Reply: Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease

Sylvie Bannwarth, Samira Ait-El-Mkadem, Annabelle Chaussenot, Emmanuelle C. Genin, Sandra Lacas-Gervais, Konstantina Fragaki, Laetitia Berg-Alonso, Yusuke Kageyama, Valérie Serre, David Moore, Annie Verschueren, Cécile Rouzier, Isabelle Le Ber, Gaëlle Augé, Charlotte Cochaud, Françoise Lespinasse, Karine N’Guyen, Anne de Septenville, Alexis Brice, Patrick Yu-Wai-Man, Hiromi Sesaki, Jean Pouget and Véronique Paquis-Flucklinger

NEK1 mutations in familial amyotrophic lateral sclerosis

Sir, Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by adult-onset loss of motor neurons. Five to 10% of all ALS cases are familial ALS. To date, more than 20 genes have been implicated in causing familial ALS, with the discovery of mutations in CHCHD10 (Bannwarth et al. , 2014) and TBK1 (Cirulli et al. , 2015; Freischmidt et al. , 2015) representing the latest examples for monogenic causes of ALS. Most recently, whole exome sequencing of ALS patients suggested an association of heterozygous loss-of-function mutations in NEK1 with ALS. However, this observation was made in a cohort of mostly sporadic patients, and the result was only significant in a combined analysis of the discovery and the replication cohort (Cirulli et al. , 2015), making further validation essential. To assess the association between NEK1 variants and familial ALS we analysed whole exome sequence data of 265 familial ALS index patients and 827 control individuals. A subset of these exome sequence data has recently led to the discovery of mutations in TBK1 as a cause for ALS in an exome-wide mutational burden analysis (Freischmidt et al. , 2015). The patients with familial ALS were selected from families with two or more affected individuals from European countries (Germany, Sweden, Finland, Denmark, Switzerland, and Portugal) following a negative screen for SOD1 and C9orf72 mutations as described previously (Freischmidt et al. , 2015). In-house control exomes ( n = 827) from Germany were used to compare the variant burden in NEK1 . All ALS patients were diagnosed according to the EFNS Consensus criteria (Andersen et al. , 2012). Control subjects were comprised of healthy parents of children with various diseases, healthy control tissues of individuals with tumour diseases and 200 individuals of the KORA study. With informed written consent and approval by …

Reward processing and intertemporal decision making in adults and adolescents: the role of impulsivity and decision consistency.

Several studies report differences between adults and adolescents in reward processing and impulsivity. Consistently, adolescents are more impulsive in their decision making, as measured by intertemporal choice tasks. Since impulsivity affects an individuals perception and neural processing of rewards, it is unclear whether previously reported differences in brain activation between adults and adolescents are primarily due to maturation of the brain reward system or differences in impulsivity (i.e. discounting behaviour). To disentangle this, we analysed data from 235 adolescents and 29 adults who performed an intertemporal choice task in which monetary rewards were adapted to individual impulsivity. Using functional magnetic resonance imaging (fMRI), we measured brain activity and assessed impulsivity and consistency of choices at the behavioural level. Although adolescents discounted delayed rewards more steeply than adults, when controlling for impulsivity, neural processing of reward value did not differ between groups. However, more impulsive subjects showed a lower brain response to delayed rewards, independent of age. Concerning decision making, adolescents exhibited a lower consistency of choices and less brain activity in the parietal network than adults. We conclude that processing of the value of prospective delayed rewards is more sensitive to discounting behaviour than to chronological age. Lower consistency of intertemporal choices might indicate ongoing maturation of parietal brain areas in adolescents.

Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization

Aggregation of α‐synuclein (α‐syn) and α‐syn cytotoxicity are hallmarks of sporadic and familial Parkinson disease (PD), with accumulating evidence that prefibrillar oligomers and protofibrils are the pathogenic species in PD and related synucleinopathies. Peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α), a key regulator of mitochondrial biogenesis and cellular energy metabolism, has recently been associated with the pathophysiology of PD. Despite extensive effort on studying the function of PGC‐1α in mitochondria, no studies have addressed whether PGC‐1α directly influences oligomerization of α‐syn or whether α‐syn oligomers impact PGC‐1α expression.

Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers

Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.

Altered Reward Processing in Adolescents With Prenatal Exposure to Maternal Cigarette Smoking

IMPORTANCE Higher rates of substance use and dependence have been observed in the offspring of mothers who smoked during pregnancy. Animal studies indicate that prenatal exposure to nicotine alters the development of brain areas related to reward processing, which might be a risk factor for substance use and addiction later in life. However, no study has examined the effect of maternal smoking on the offsprings brain response during reward processing. OBJECTIVE To determine whether adolescents with prenatal exposure to maternal cigarette smoking differ from their nonexposed peers in the response of the ventral striatum to the anticipation or the receipt of a reward. DESIGN An observational case-control study. SETTING Data were obtained from the IMAGEN Study, a European multicenter study of impulsivity, reinforcement sensitivity, and emotional reactivity in adolescents. The IMAGEN sample consists of 2078 healthy adolescents (age range, 13-15 years) recruited from March 1, 2008, through December 31, 2011, in local schools. PARTICIPANTS We assessed an IMAGEN subsample of 177 adolescents with prenatal exposure to maternal cigarette smoking and 177 nonexposed peers (age range, 13-15 years) matched by sex, maternal educational level, and imaging site. MAIN OUTCOME AND MEASURE Response to reward in the ventral striatum measured with functional magnetic resonance imaging. RESULTS In prenatally exposed adolescents, we observed a weaker response in the ventral striatum during reward anticipation (left side, F = 14.98 [P < .001]; right side, F = 15.95 [P < .001]) compared with their nonexposed peers. No differences were found regarding the responsivity of the ventral striatum to the receipt of a reward (left side, F = 0.21 [P = .65]; right side, F = 0.47 [P = .49]). CONCLUSIONS The weaker responsivity of the ventral striatum to reward anticipation in prenatally exposed adolescents may represent a risk factor for substance use and development of addiction later in life. This result highlights the need for education and preventive measures to reduce smoking during pregnancy. Future analyses should assess whether prenatally exposed adolescents develop an increased risk for substance use and addiction and which role the reported neuronal differences during reward anticipation plays in this development.