Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life ...and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein-Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced the hyperexcitability in the lymphoblast-derived LR group but not in the NR group, strengthening the validity and utility of this new human cellular model of BD.
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in ...sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. ...It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann–Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) 2.85 μmol/l/h versus 3.12 μmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls), and when including the entire cohort (2.89 μmol/l/h versus 3.10 μmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 μmol/l/h versus 3.10 μmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31–0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.
•Activity was measured for 5 lysosomal enzymes in blood spots of PD and controls.•Alpha galactosidase A (deficient in Fabry disease) activity is reduced in PD cases.•Alpha galactosidase A and acid sphingomylinase are elevated in LRRK2 carriers.
•Neuropsychiatric disorders display aberrant posttranslational modifications (PTM).•Lithium - a therapeutic agent for neurodegenerative and neuropsychiatric disorders.•Outline of the links between ...lithium’s therapeutic mode of action and PTM homeostasis.•Posttranslational modifications as a hub for disease markers and lithium responsiveness.
Several neurodegenerative diseases and neuropsychiatric disorders display aberrant posttranslational modifications (PTMs) of one, or many, proteins. Lithium treatment has been used for mood stabilization for many decades, and is highly effective for large subsets of patients with diverse neurological conditions. However, the differential effectiveness and mode of action are not fully understood. In recent years, studies have shown that lithium alters several protein PTMs, altering their function, and consequently neuronal physiology. The impetus for this review is to outline the links between lithium’s therapeutic mode of action and PTM homeostasis. We first provide an overview of the principal PTMs affected by lithium. We then describe several neuropsychiatric disorders in which PTMs have been implicated as pathogenic. For each of these conditions, we discuss lithium’s clinical use and explore the putative mechanism of how it restores PTM homeostasis, and thereby cellular physiology. Evidence suggests that determining specific PTM patterns could be a promising strategy to develop biomarkers for disease and lithium responsiveness.
Mutations in the TARDBP gene, which encodes the TAR DNA binding protein (TDP-43), have been described in individuals with familial and sporadic amyotrophic lateral sclerosis (ALS). We screened the ...TARDBP gene in 285 French sporadic ALS patients to assess the frequency of TARDBP mutations in ALS.
Six individuals had potentially deleterious mutations of which three were novel including a Y374X truncating mutation and P363A and A382P missense mutations. This suggests that TARDBP mutations may predispose to ALS in approximately 2% of the individuals followed in this study.
Our findings, combined with those from other collections, brings the total number of mutations in unrelated ALS patients to 17, further suggesting that mutations in the TARDBP gene have an important role in the pathogenesis of ALS.
Abstract Trinucleotide repeat expansions have been associated with many neurodegenerative diseases, developmental disorders and muscular dystrophies. Among those triplet repeat expansions, ...polyalanine tract elongations are associated with early developmental abnormalities with the exception of OPMD, a late onset muscular dystrophy. This review presents an overview of recent advances on the molecular mechanisms underlying the group of polyalanine diseases and provides insights into the pathological impact of polyalanine tract expansion on protein dysfunction. While hydrophobic polyalanine tracts in the normal range are considered to be flexible spacers that confer stability and flexibility to the protein three-dimensional conformation, expanded polyalanine repeats are thought to destabilize the native conformation of the protein and alter protein levels and activity. Protein dysfunction following polyalanine expansion has been reported to cause transcriptional dysregulation which may delay early developmental processes or induce cytotoxicity in polyalanine disease models.
Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the ...hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).
Dominant mutations in PIEZO2, which codes for the principal mechanotransduction channel for proprioception and touch sensation, have been found to cause different forms of distal arthrogryposis. Some ...observations suggest that these dominant mutations induce a gain‐of‐function effect on the channel. Here, we report a consanguineous family with three siblings who showed short stature, scoliosis, gross motor impairment, and a progressive form of contractures involving the distal joints that is distinct from that found in patients with dominant mutations in PIEZO2. These siblings also displayed deficits in proprioception and touch sensation. Whole‐exome sequencing performed in the three affected siblings revealed the presence of a rare homozygous variant (c.2708C>G; p.S903*) in PIEZO2. This variant is predicted to disrupt PIEZO2 function by abolishing the pore domain. Sanger sequencing confirmed that all three siblings are homozygous whereas their parents and an unaffected sibling are heterozygous for this variant. Recessive mutations in PIEZO2 thus appear to cause a progressive phenotype that overlaps with, while being mostly distinct from that associated with dominant mutations in the same gene.
Identification of a homozygous truncating PIEZO2 mutation in three affected siblings from a consanguineous family showing short stature, scoliosis, gross motor impairment, a progressive form of contractures involving the distal joints and deficits in proprioception and touch sensation.
ABSTRACT
Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP‐43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP‐43 positive inclusion ...bodies were first discovered in ubiquitin‐positive, tau‐negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C‐terminus of the proteins. The molecular mechanisms through which mutant TDP‐43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance, and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here have been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS.
Amyotrophic Lateral Sclerosis is a progressive and devastating disorder of motor neurons. A number of genes have been found commonly mutated in ALS patients. Among these, TARDBP and FUS play an important role. Both proteins are involved in mRNA transport, axonal maintenance and motor neuron development but the exact molecular mechanisms through which they cause motor neuron degeneration, when mutated, are not well understood. This report summarizes the genetic, biological and clinical relevance of TARDBP and FUS mutations in ALS.
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