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Background: Tourette syndrome is a developmental neuropsychiatric disorder. Its etiology is complex and elusive, although an important role of genetic factors has been established. The aim of the present study was to identify the genomic basis of Tourette syndrome in a group of families with affected members in 2 or 3 generations. Methods: Whole-genome sequencing was performed followed by co-segregation and bioinformatic analyses. Identified variants were used to select candidate genes, which were then subjected to gene ontology and pathway enrichment analysis. Results: The study group included 17 families comprising 80 patients with Tourette syndrome and 44 healthy family members. Co-segregation analysis and subsequent prioritization of variants pinpointed 37 rare and possibly pathogenic variants shared among affected individuals within a single family. Three such variants, in the ALDH2, DLD and ALDH1B1 genes, could influence oxidoreductase activity in the brain. Two variants, in SLC17A8 and BSN genes, were involved in sensory processing of sound by inner hair cells of the cochlea. Enrichment analysis of genes whose rare variants were present in all patients from at least 2 families identified significant gene sets implicated in cell-cell adhesion, cell junction assembly and organization, processing of sound, synapse assembly, and synaptic signalling processes. Limitations: We did not examine intergenic variants, but they still could influence clinical phenotype. Conclusion: Our results provide a further argument for a role of adhesion molecules and synaptic transmission in neuropsychiatric diseases. Moreover, an involvement of processes related to oxidative stress response and sound-sensing in the pathology of Tourette syndrome seems likely., Introduction Tourette syndrome is a neurodevelopmental disorder characterized by motor and vocal/phonic tics persisting for longer than a year. The clinical phenotype of Tourette syndrome belongs to the spectrum of [...]

Tau inclusions are a shared feature of many neurodegenerative diseases, among them frontotemporal dementia caused by tau mutations. Treatment approaches for these conditions include targeting posttranslational modifications of tau proteins, maintaining a steady-state amount of tau, and preventing its tendency to aggregate. We discovered a new regulatory pathway for tau degradation that operates through the farnesylated protein, Rhes, a GTPase in the Ras family. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib reduced Rhes and decreased brain atrophy, tau inclusions, tau sumoylation, and tau ubiquitination in the rTg4510 mouse model of tauopathy. In addition, lonafarnib treatment attenuated behavioral abnormalities in rTg4510 mice and reduced microgliosis in mouse brain. Direct reduction of Rhes in the rTg4510 mouse by siRNA reproduced the results observed with lonafarnib treatment. The mechanism of lonafarnib action mediated by Rhes to reduce tau pathology was shown to operate through activation of lysosomes. We finally showed in mouse brain and in human induced pluripotent stem cell-derived neurons a normal developmental increase in Rhes that was initially suppressed by tau mutations. The known safety of lonafarnib revealed in human clinical trials for cancer suggests that this drug could be repurposed for treating tauopathies.

Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibrils dissolution and abnormal accumulation of degradation products. So far causative mutations have been identified in nine genes encoding Z-disk proteins, including αB-crystallin (CRYAB), a small heat shock protein (also called HSPB5). Here, we report a case study of a 63-year-old Polish female with a progressive lower limb weakness and muscle biopsy suggesting a myofibrillar myopathy, and extra-muscular multisystemic involvement, including cataract and cardiomiopathy. Five members of the proband's family presented similar symptoms. Whole exome sequencing followed by bioinformatic analysis revealed a novel D109A mutation in CRYAB associated with the disease. Molecular modeling in accordance with muscle biopsy microscopic analyses predicted that D109A mutation influence both structure and function of CRYAB due to decreased stability of oligomers leading to aggregate formation. In consequence disrupted sarcomere cytoskeleton organization might lead to muscle pathology. We also suggest that mutated RQDE sequence of CRYAB could impair CRYAB chaperone-like activity and promote aggregation of lens crystallins.

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and vocal tics. The etiology of the disorder is unknown, although the predominant role of genetic factors has been established. Variants of the BTBD9 gene (rs4714156, rs9296249 and rs9357271) have been reported to be associated with GTS in French Canadian and Chinese Han populations. Therefore, we decided to test the association between GTS and polymorphisms of the BTBD9 gene in Polish patients. Our cohort of GTS cases comprised 162 patients aged 4-54 years (mean age: 19.9 ± 8.7 years; 131 males, 80.9 percent). The control group consisted of 180 healthy persons aged 14-55 years (mean age: 23.1 ± 2.1 years; 149 males, 82.8 percent). The rs4714156, rs9296249 and rs9357271 variants of the BTBD9 gene were genotyped. No significant differences were found in minor allele frequencies (MAFs) of the SNPs tested between the two groups. The frequency of MAFs of the genotyped SNPs was lower in GTS patients with Attention Deficit Hyperactivity Disorder (for rs9357271 and rs9296249, P=0.039 and rs4714156, P=0.040) and higher in GTS patients without comorbidities (for rs9357271 and rs9296249 P=0.021 and rs4714156 P=0.025). There was a trend toward an association between the minor allele of the SNPs and mild tics (P=0.089 for rs9357271 and rs9296249, P=0.057 for rs4714156). Despite limitations of the study, including the small number of cases and analyzed SNPs, our results suggest that the examined BTBD9 variants are not associated with GTS risk, but may be associated with comorbidity and tic severity in the Polish population.

Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R) mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i) we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii) the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment.

TDP-43, a newly described neurodegenerative protein, is of great interest to both neurologists and geneticists. At the beginning, its dysfunction was recognized in sporadic amyotrophic lateral sclerosis, frontotemporal lobar degeneration with ubiquitinated inclusions and in mixed forms. However, it was also proved that TDP-43 inclusions are in addition present in many other diseases, for example in inclusion body myositis. Furthermore, many genes and different loci may be involved in pathological TDP-43 accumulation in cells and tissues. Mutations in the TARDPB gene, progranulin gene (PGRNVCP) as well as a gene on chromosome 9p were found. The present paper is a summary on possible involvement of TDP-43 in various neurodegenerative disorders.

Background: Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1) plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD) and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk., Methods: We performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD) patients in comparison with healthy controls., Results: Analysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk.In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed., Conclusion: Our data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.

A critical role of mitochondrial dysfunction and oxidative damage has been implicated in etiopathology of many neurodegenerative disorders, as well as in normal aging. Alzheimer's and Parkinson's diseases are common devastating late-onset neurodegenerative disorders, associated with mitochondrial DNA variations, which are suggested to affect mitochondrial functions. This paper reviews the current knowledge on the inherited and somatic mtDNA variations in both conditions.