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Mutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower motor neurons. The clinical phenotype of ALS shows inter- and intrafamilial heterogeneity. The aim of the study was to analyze the relations between individual SOD1 mutations and the clinical presentation using in silico methods to assess the SOD1 mutations severity. We identified SOD1 causative variants in a group of 915 prospectively tested consecutive Polish ALS patients from a neuromuscular clinical center, performed molecular modeling of mutated SOD1 proteins and in silico analysis of mutation impact on clinical phenotype and survival analysis of associations between mutations and hazard of clinical end-points. Fifteen SOD1 mutations were identified in 21.1% familial and 2.3% sporadic ALS cases. Their effects on SOD1 protein structure and functioning inferred from molecular modeling and in silico analyses correlate well with the clinical data. Molecular modeling results support the hypothesis that folding intermediates rather than mature SOD1 protein give rise to the source of cytotoxic conformations in ALS. Significant associations between type of mutation and clinical end-points were found.

Background: Homozygous variants of the TREM2 and TYROBP genes have been shown to be causative for multiple bone cysts and neurodegeneration leading to progressive dementia (NHD, Nasu-Hakola disease). Objective: To determine if biallelic variants of these genes and/or oligogenic inheritance could be responsible for a wider spectrum of neurodegenerative conditions. Methods: We analyzed 52 genes associated with neurodegenerative disorders using targeted next generation sequencing in a selected group of 29 patients (n = 14 Alzheimer’s disease, n = 8 frontotemporal dementia, n = 7 amyotrophic lateral sclerosis) carrying diverse already determined rare variants in exon 2 of TREM2. Molecular modeling was used to get an insight into the potential effects of the mutation. Results: We identified a novel mutation c.401_406delinsTCTAT; p.(Asp134Valfs*55) in exon 3 of TREM2 in an Alzheimer’s disease patient also carrying the p.Arg62His TREM2 variant. Molecular modeling revealed that the identified mutation prevents anchoring of the TREM2 protein in the membrane, leaving the core of the Ig-like domain intact. Conclusion: Our results expand the spectrum of neurodegenerative diseases, where the carriers of biallelic mutations in TREM2 have been described for Alzheimer’s disease, and highlight the impact of variant burden in other genes on phenotypic heterogeneity.

Numerous genetic factors have been shown to influence athletic performance, but the list is far from comprehensive. In this study, we analyzed genetic variants in two genes related to mental abilities, SLC6A2 (rs1805065) and SYNE1 (rs2635438) in a group of 890 athletes (320 endurance, 265 power, and 305 combat athletes) vs. 1009 sedentary controls. Genotyping of selected SNPs was performed using TaqMan SNP genotyping assays. SLC6A2 codes for norepinephrine transporter, a protein involved in modulating mood, arousal, memory, learning, and pain perception, while SYNE1 encodes protein important for the maintenance of the cerebellum—the part of the brain that coordinates complex body movements. Both SNPs (rs2635438 and rs1805065) showed no statistically significant differences between the frequencies of variants in the athletes and the sedentary controls (athletes vs. control group) or in the athlete subgroups (martial vs. control, endurance vs. control, and power vs. control). The rs1805065 T variant of SLC6A2 was found to be overrepresented in male high-elite martial sports athletes when compared to sedentary controls (OR = 6.56, 95%CI = 1.82–23.59, p = 0.010). This supports the hypothesis that genetic variants potentially affecting brain functioning can influence elite athletic performance and indicate the need for further genetic association studies, as well as functional analyses.

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with TDP-43 mislocalization and aggregation. Genetic forms of FTLD and ALS are caused by pathogenic variants in various genes, such as PGRN (progranulin). To date, depletion of parkin E3 ubiquitin protein ligase, a key mitophagy regulator, has been reported in sporadic ALS patients and ALS mice models with TDP-43 proteinopathy. In this work, we show parkin downregulation also in fibroblasts derived from FTLD patients with four different PGRN pathogenic variants. We corroborate this finding in control fibroblasts upon PGRN silencing, demonstrating additionally the decrease of parkin downstream targets, mitofusin 2 (MFN2) and voltage dependent anion channel 1 (VDAC1). Importantly, we show that TDP-43 overexpression rescues PRKN levels upon transient PGRN silencing, but not in FTLD fibroblasts with PGRN pathogenic variants, despite upregulating PGRN levels in both cases. Further observation of PRKN downregulation upon TDP-43 silencing, suggests that TDP-43 loss-of-function contributes to PRKN decrease. Our results provide further evidence that parkin downregulation might be a common and systemic phenomenon in neurodegenerative diseases with TDP- 43 loss-of-function.

In all sport disciplines, excellent coordination of movements is crucial for achieving mastery. The ability to learn new motor skills quickly and effectively is dependent on efficient myelination which varies between individuals. It has been suggested that these differences may play a role in athletic performance. The process of myelination is under transcriptional control by Myelin Regulatory Factor (MYRF) as well as other transcription factors (SOX10 and OLIG2). We analyze a panel of 28 single nucleotide polymorphisms (SNPs) located within the frequencies of common variants of MYRF, SOX10 and OLIG2 genes in professional athletes compared to non-athletes. No significant differences were detected after correction for multiple testing by false discovery rate (FDR) for any of the models tested. However, some deviations from the expected distribution was found for seven SNPs (rs174528, rs139884, rs149435516 and rs2238001, rs7943728, rs61747222, and rs198459). The MYRF alleles rs7943728 and rs61747222 showed a correlation with the level of sport achievement among the athletes. Even though the athletes did not differ from the non-athlete controls in the distribution of most SNPs analyzed, some interesting differences of several variants were noted. Presented results indicate that genetic variants of MYRF and SOX10 could be genetic factors weakly predisposing for successful athletic performance.

Background: ALDH3A1 protein is important in maintaining corneal physiology and protecting the eye from UV damage. However, none of the genome-wide association studies has indicated that the ALDH3A1 locus is associated with keratoconus. In this study, we examined the potential role of ALDH3A1 variants as risk factors for keratoconus incidence and severity in a large group of Polish keratoconus patients. Methods: In the first stage we analyzed the coding region sequence of the ALDH3A1 in a subgroup of keratoconus. Then, we genotyped three selected ALDH3A1 variants in a larger KC group of patients (n = 261) and healthy controls (n = 317). Results: We found that the rs1042183 minor allele A is a risk factor for keratoconus in the dominant model (OR = 2.06, 95%CI = 1.42–2.98, p = 0.00013). The rs2228100 variant genotypes appear to be associated with an earlier age of KC diagnosis in the Polish population (p = 0.055 for comparison of three genotypes and p = 0.022 for the dominant inheritance model). Conclusions: The rs1042183 variant in ALDH3A1 is associated with keratoconus risk in the Polish population. The differences in the allele frequency between both populations could be partially responsible for the difference in the disease prevalence.

We have performed whole-genome sequencing to identify the genetic variants potentially contributing to the early-onset semantic dementia phenotype in a patient with family history of dementia and episodic memory deficit accompanied with profound semantic loss. Only very rare variants of unknown significance (VUS) have been identified: a nonsense variant c.366C>A/p.Cys122* in plasminogen activator, urokinase (PLAU) and a missense variant c.944C>T/p.Thr315Met in β-site APP-cleaving enzyme 1 (BACE1)—along with known disease-modifying variants of moderate penetrance. Patient-derived fibroblasts showed reduced PLAU and elevated BACE1 mRNA and protein levels compared to control fibroblasts. Successful rescue of PLAU mRNA levels by nonsense-mediated mRNA decay (NMD) inhibitor (puromycin) confirmed NMD as the underlying mechanism. This is the first report of the PLAU variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. Our results suggest that rare variants in the PLAU and BACE1 genes should be considered in future studies on early-onset dementias.

Activation of the TREM2 receptor on microglia stimulates phagocytosis and decreases the microglial proinflammatory response. Mutations in exon 2 of the TREM2 gene have been reported to be associated with various neurodegenerative diseases characterized by chronic inflammation. The aim of our study was to evaluate exon 2 of TREM2 gene variants as a putative genetic risk factor for Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) in the Polish population. The results were interpreted using previously published data, especially highlighting differences in the prevalence of the variants among Caucasian subpopulations across different geographic regions. The DNA sequence of exon 2 of TREM2 was analyzed in 811 subjects (274 AD, 135 FTD, 194 ALS patients, and 208 neurologically healthy controls). Nine heterozygous variants were detected, including two novel ones: p.G29 = and c.41-2_3insA, found respectively in a control and an ALS patient. Additionally, we identified one homozygous and two compound heterozygous FTD patients. We confirm previous data that homozygous and compound heterozygous TREM2 mutations can be causative for FTD.

Objective: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. Methods: Blood samples from 4072 individuals, ALS patients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed. Coding SOD1 sequences were analysed by Sanger sequencing, exon copy number variations by fragment length analysis and by TaqMan Assay. Results: Of the 44 SOD1 mutations found, 75% caused severe destabilisation of the mutant protein but in 25% it was physically stable. Mutations producing structural changes caused halved erythrocyte SOD1 activities. There were no differences in SOD1 activities between patients without a SOD1 mutation and control individuals or carriers of TBK1 mutations and C9orf72HRE. In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Thalassemias and iron deficiency were associated with increased SOD1 activity/haemoglobin ratios. Conclusion: Adjunct erythrocyte SOD1 activity analysis reliably signals destabilising SOD1 mutations including intronic mutations that are missed by exon sequencing.

Introduction Sporadic inclusion body myositis (sIBM) is one of the most common myopathies in patients above 50 years of age. Its progressive course finally leads to immobilisation, and no effective therapy exists. Its pathogenesis includes both degenerative and inflammatory processes, however, its direct causes remain unknown. Therefore, a possible genetic background of the disease must also be considered. Material and methods Here we report on twelve patients: eight with sporadic inclusion body myositis and four with other myopathies with rimmed vacuoles in muscle biopsy. All patients were evaluated clinically, morphologically, radiologically, and genetically. Results All patients with sIBM presented both shoulder and pelvic girdle muscle involvement. In addition, distal upper and lower limb muscle weakness was noted. Patients with other muscle disorders showed effects mainly in proximal muscles and marked calf muscle hypertrophy. In sIBM cases computed tomography of lower limb muscles revealed atrophy that was most pronounced within the quadriceps femoris and gracilis muscles in the thighs and within the medial head of the gastrocnemius muscle and the tibialis anterior muscle in the lower legs. On light microscopy mononuclear cell invasion of muscle fibres was present in six patients with sIBM. On electron microscopy myofibrillar disorganisation and mitochondrial abnormalities were noted in all sIBM patients, whereas cytoplasmic tubulofilamentous inclusions were seen in three patients and both cytoplasmic and nuclear inclusions in one of them. According to the criteria by Rose et al. (2011) six patients were classified as "clinico-pathologically defined IBM", one as "clinically defined IBM", and one as "probable IBM". Pathological deposits of TDP-43 were found in muscles in all sIBM as well as in control cases. Additionally, accumulation of other proteins thought to be associated with sIBM, like β-amyloid, -synuclein, and tau protein, was present in the most of examined biopsies. All twelve patients were screened for the presence of causative mutations in TARDBP, VCP, HNRNPA1, and HNRNPA2B1 genes. Additionally, analysis of C9ORF72 hexanucleotide repeat expansion was performed. No causative mutations were found in any of the patients. Conclusions Our study provides the first - to our knowledge - comprehensive clinical, pathological, and genetic workup of a group of Polish patients.

Myosin VI (MVI) is a unique unconventional myosin translocating, unlike other myosins, towards the minus end of actin filaments. It is involved in numerous cellular processes such as endocytosis, intracellular trafficking, cell migration, and transcription. In mammalian skeletal muscles it localizes mainly to sarcoplasmic reticulum and is also present within the muscle nuclei and at the neuromuscular junction (Karolczak et al. Histochem Cell Biol 2013; 23:219-228). We have also shown that in denervated rat hindlimb muscle the MVI expression level is significantly increased and its localization is changed, indicating an important role of MVI in striated muscle pathology. Here, we addressed this problem by examining the distribution and expression levels of myosin VI in biopsies of skeletal muscles from patients with different myopathies. We found that, particularly in myopathies associated with fiber atrophy, the amount of MVI was enhanced and its localization in affected fibers was changed. Also, since a mutation within the human MVI gene was shown to be associated with cardiomyopathy, we assessed MVI localization and expression level in cardiac muscle using wild type and MLP(-/-) mice, a dilated cardiomyopathy model. No significant difference in MVI expression level was observed for both types of animals. MVI was found at intercalated discs and also at the sarcoplasmic reticulum. In the knockout mice, it was also present in ring-like structures surrounding the nuclei. The data indicate that in striated muscle MVI could be engaged in sarcoplasmic reticulum maintenance and/or functioning, vesicular transport, signal transmission and possibly in gene transcription.

Frontotemporal lobar degeneration (FTLD) with mutations in the MAPT (microtubule-associated protein tau) gene (FTLD with MAPT mutation) is a neurodegenerative disease with various clinical phenotypes. We present an ItalianPolish family with a IVS10+3G>A mutation in the MAPT gene, linked with haplotype H1s in a male proband (Fig. 2, II.2, H1s/H1b diplotype) and his sister (Fig. 2, II.1, the H1s/H1j diplotype). This report presents clinical, neuropathological and genetic testing of the proband and his affected sister, two members of an Italian-Polish family consisting of 25 family members. Their clinical history includes dementia as well as movement and cardiovascular disorders. Magnetic resonance imaging showed frontal and temporal cerebral atrophy. Neuropathological studies of the brain samples showed loss of neurons, gliosis, and the occurrence of neurofibrillary tangles, numerous neuropil threads, coiled bodies and abundant deposits of tau protein, including 3- and 4-repeated isoforms in neurons and glial cells. Only in the male proband brain, there were Pick body-like deposits in granule neurons of the hippocampus. Pathology of vascular walls was found in both cases. Ultrastructurally, the male proband showed clusters of collagen fibers mainly in a pericyte position. Beside the typical neurofibrillary pathology, aggregated gliofilaments and lipofuscin deposits in astroglia are described. Our report suggests that FTLD with IVS10+3G>A MAPT mutation causes damage mainly to the central nervous system and induces neuropathological changes, depending on the haplotypes of MAPT. In the clinical course of this disease, damage of the cardiovascular system may also be observed.

Cu/Zn superoxide dismutase (SOD1) gene mutations are the most frequently reported genetic causes of amyotrophic lateral sclerosis (ALS). The objective of the study was to describe a clinical phenotype and haplotype background of Polish and Japanese ALS patients harbouring the K3E SOD1 mutation. The K3E mutation was identified by direct sequencing, high resolution melting analysis or high-throughput microarray-based resequencing system. Microsatellite polymorphic markers flanking SOD1 were genotyped in members of six kindreds and two SALS patients. Results demonstrated that the K3E mutation was responsible for classic ALS. The median age of onset was 54 years. The clinical phenotype did not substantially differ between SALS and FALS cases of either ethnic origin, with some intrafamiliar variabilities. There was a limb onset in 92% of patients. In patients with bulbar syndrome, dysphagia predominated over dysarthria. Respiratory insufficiency was found in 61.1% of patients (19-84 months after the first symptoms onset). Median survival was 101 months with age of death ranging from 45 to 77 years. K3E was the most frequent SOD1 mutation among Polish FALS patients. It originated independently, on different haplotype background in the Polish and Japanese populations. In conclusion, recurrent K3E mutation results in a relatively slowly progressing limb onset ALS with classic phenotype.

Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L), which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may reflect the limitations of these tests used and the sample sizes, olfactory dysfunction appears to be associated with the inability to identify odors reliably and consistently, not with the loss of an ability to identify specific odors. Irreproducibility in odor identification appears to be a non-disease-specific, general feature of olfactory dysfunction that is accelerated or accentuated in neurodegenerative disease. It may reflect a fundamental organizational principle of the olfactory system, which is more "error-prone" than other sensory systems.

Streszczenie W ostatnich latach szczegolne zainteresowanie zarowno neurologow, jak i genetykow wzbudza bialko TDP-43. Zaburzenia jego funkcji wiązano początkowo z postacią sporadyczną stwardnienia bocznego zanikowego i zwyrodnienia czolowo–skroniowego z wtretami ubikwitynowanymi oraz postaciami mieszanymi zwyrodnienia czolowo-skroniowego. Udowodniono jednak, ze do gromadzenia zlogow zlozonych z TDP-43 dochodzi rowniez w innych chorobach, m.in. we wtretowym zapaleniu mieśni. Wykazano, ze mogą za to odpowiadac mutacje w kilku genach i loci: w genie TARDPB , genie progranuliny ( PGRN ) czy genie bialka zawierającego walozyne ( valosin-containing protein, VCP ), a takze w niezidentyfikowanym genie polozonym na chromosomie 9p. Niniejsza praca stanowi podsumowanie dotychczasowej wiedzy na temat roli TDP-43 w procesach neurodegeneracyjnych.

Mutations in the superoxide dismutase-1 (SOD1) gene have been found in 12-23% of patients with a diagnosis of ALS. Here we describe a large ALS Polish family with a branch in France, carrying a G41S mutation in the SOD1, and characterized by an early onset of the disease and extremely short survival time. The mutation has been initially detected in Italian ALS families with common founder effect. However, in the Polish population the G41S mutation most probably originated from an independent mutation event, as indicated by haplotype analysis. Collected data support the hypothesis that a SOD1 mutation is not the sole factor determining the clinical ALS phenotype.

Frontotemporal lobar degeneration (FTLD) with mutations in the MAPT (microtubule-associated protein tau) gene (FTLD with MAPT mutation) is a neurodegenerative disease with various clinical phenotypes. We present an Italian- Polish family with a IVS10+3GA mutation in the MAPT gene, linked with haplotype H1s in a male proband (Fig. 2, II.2, H1s/H1b diplotype) and his sister (Fig. 2, II.1, the H1s/H1j diplotype). This report presents clinical, neuropathological and genetic testing of the proband and his affected sister, two members of an Italian-Polish family consisting of 25 family members. Their clinical history includes dementia as well as movement and cardiovascular disorders. Magnetic resonance imaging showed frontal and temporal cerebral atrophy. Neuropathological studies of the brain samples showed loss of neurons, gliosis, and the occurrence of neurofibrillary tangles, numerous neuropil threads, coiled bodies and abundant deposits of tau protein, including 3- and 4-repeated isoforms in neurons and glial cells. Only in the male proband brain, there were Pick body-like deposits in granule neurons of the hippocampus. Pathology of vascular walls was found in both cases. Ultrastructurally, the male proband showed clusters of collagen fibers mainly in a pericyte position. Beside the typical neurofibrillary pathology, aggregated gliofilaments and lipofuscin deposits in astroglia are described. Our report suggests that FTLD with IVS10+3GA MAPT mutation causes damage mainly to the central nervous system and induces neuropathological changes, depending on the haplotypes of MAPT. In the clinical course of this disease, damage of the cardiovascular system may also be observed.

Objectives: Patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) may be agraphic. The study aimed at characterizing agraphia in individuals with a P301L MAPT mutation.Methods: Two pairs of siblings with FTDP-17 were longitudinally examined for agraphia in relation to language and cognitive deficits.Results: All patients presented with dysexecutive agraphia. In addition, in the first pair of siblings one sibling demonstrated spatial agraphia with less pronounced allographic agraphia and the other sibling had aphasic agraphia. Aphasic agraphia was also present in one sibling from the second pair.Conclusion: Agraphia associated with FTDP-17 is very heterogeneous.

Desmin is a muscle-specific intermediate filament protein which forms a network connecting the sarcomere, T tubules, sarcolemma, nuclear membrane, mitochondria and other organelles. Mutations in the gene coding for desmin (DES) cause skeletal myopathies often combined with cardiomyopathy, or isolated cardiomyopathies. The molecular pathomechanisms of the disease remain ambiguous. Here, we describe and comprehensively characterize two DES mutations found in Polish patients with a clinical diagnosis of desminopathy. The study group comprised 16 individuals representing three families. Two mutations were identified: a novel missense mutation (Q348P) and a small deletion of nine nucleotides (A357_E359del), previously described by us in the Polish population. A common ancestry of all the families bearing the A357_E359del mutation was confirmed. Both mutations were predicted to be pathogenic using a bioinformatics approach, including molecular dynamics simulations which helped to rationalize abnormal behavior at molecular level. To test the impact of the mutations on DES expression and the intracellular distribution of desmin muscle biopsies were investigated. Elevated desmin levels as well as its atypical localization in muscle fibers were observed. Additional staining for M-cadherin, α-actinin, and myosin heavy chains confirmed severe disruption of myofibrill organization. The abnormalities were more prominent in the Q348P muscle, where both small atrophic fibers as well large fibers with centrally localized nuclei were observed. We propose that the mutations affect desmin structure and cause its aberrant folding and subsequent aggregation, triggering disruption of myofibrils organization.

Myosin VI (MVI) is a unique unconventional myosin translocating, unlike other myosins, towards the minus end of actin filaments. It is involved in numerous cellular processes such as endocytosis, intracellular trafficking, cell migration, and transcription. In mammalian skeletal muscles it localizes mainly to sarcoplasmic reticulum and is also present within the muscle nuclei and at the neuromuscular junction (Karolczak et al. Histochem Cell Biol 2013; 23:219-228). We have also shown that in denervated rat hindlimb muscle the MVI expression level is significantly increased and its localization is changed, indicating an important role of MVI in striated muscle pathology. Here, we addressed this problem by examining the distribution and expression levels of myosin VI in biopsies of skeletal muscles from patients with different myopathies. We found that, particularly in myopathies associated with fiber atrophy, the amount of MVI was enhanced and its localization in affected fibers was changed. Also, since a mutation within the human MVI gene was shown to be associated with cardiomyopathy, we assessed MVI localization and expression level in cardiac muscle using wild type and MLP(-/-) mice, a dilated cardiomyopathy model. No significant difference in MVI expression level was observed for both types of animals. MVI was found at intercalated discs and also at the sarcoplasmic reticulum. In the knockout mice, it was also present in ring-like structures surrounding the nuclei. The data indicate that in striated muscle MVI could be engaged in sarcoplasmic reticulum maintenance and/or functioning, vesicular transport, signal transmission and possibly in gene transcription.

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.

Centronuclear myopathies constitute a group of heterogeneous congenital myopathies characterized by the presence of abnormal, centrally located nuclei within muscle fibers. Centronuclear myopathies can be caused by mutations of several different genes, including DNM2, encoding dynamin 2 (DNM2) a large GTPase involved in membrane trafficking and endocytosis. We report a 52-year-old female with slowly progressive muscle weakness, and a family history of the disease. Clinical, morphological, biochemical and genetic analyses of the proband and her family members were performed, including analyses of the proband's muscle biopsy. A novel D614N mutation, located in the C-terminal region pleckstrin-homology (PH) domain of DNM2 was identified in the proband and four family members, who exhibited similar symptoms. The mutation was associated with profound changes in the localization of DNM2 in muscle fibers without significant changes in protein expression. Mutated DNM2 and proteins involved in the membrane trafficking or membrane compartments maintenance were dislocalized within the myofiber, and concentrated at centrally located nuclei. This novel causative mutation (D614N) within the DNM2 gene in a large Polish centronuclear myopathy family with a late age of overt clinical manifestation caused profound changes in DNM2 localization and impaired proper organization of myofibers, and skeletal muscle functioning.

Frontotemporal dementia (FTD) is one of the commonest forms of early-onset dementia, accounting for up to 20% of all dementia patients. Recently, it has been shown that mutations in progranulin gene (PGRN) cause many familial cases of FTD. Members of a family affected by FTD spectrum disorders were ascertained in Poland and Canada. Clinical, radiological, molecular, genetic, and pathological studies were performed. A sequencing analysis of PGRN exons 1-13 was performed in the proband. Genotyping of the identified PGRN mutation and pathological analysis was carried out in the proband's brother. The onset of symptoms of FTD in the proband included bradykinesia, apathy, and somnolence followed by changes in personality, cognitive deficits, and psychotic features. The proband's clinical diagnosis was FTD and parkinsonism (FTDP). DNA sequence analysis of PGRN revealed a novel, heterozygous mutation in exon 11 (g.2988_2989delCA, P439_R440fsX6). The mutation introduced a premature stop codon at position 444. The proband's brother with the same mutation had a different course first presenting as progressive non-fluent aphasia, and later evolving symptoms of behavioral variant of FTD. He also developed parkinsonism late in the disease course evolving into corticobasal syndrome. Pathological analysis in the brother revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/TDP-43 positive pathology. The novel PGRN mutation is a disease-causing mutation and is associated with substantial intra-familial clinical heterogeneity. Although presenting features were different, rapid and substantial deterioration in the disease course was observed in both family members.

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.

Background Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and vocal tics. Hyperactivity of dopaminergic transmission is considered a prime abnormality in the pathophysiology of tics. There are reciprocal antagonistic interactions between adenosine and dopamine transmission. The aim of the study was to analyze the association of two polymorphisms, rs2228079 in ADORA1 and rs5751876 in ADORA2A, with the risk of GTS and co-morbid disorders. Material and Methods A total of 162 Polish GTS patients and 270 healthy persons were enrolled in the study. Two polymorphisms were selected on the basis of knowledge of SNPs frequencies in ADORA1 and ADORA2A. Chi-square test was used for allelic and genotypic association studies. Association of genotypes with age of tic onset was analyzed with Mann-Whitney test. Multivariate logistic regression was used to find independent predictors of GTS risk. Results We found that the risk of GTS was associated with rs2228079 and rs5751876 polymorphisms. The GG+GT genotypes of rs2228079 in ADORA1 were underrepresented in GTS patients (p = 0.011), whereas T allele of rs5751876 in ADORA2A was overrepresented (p = 0.017). The GG genotype of rs2228079 was associated with earlier age of tic onset (p = 0.046). We found also that the minor allele G of rs2228079 was more frequent in GTS patients with depression as compared to the patients without depression (p = 0.015). Also the genotype GG was significantly more frequent in patients with obsessive compulsive disorder/behavior (OCD/OCB, p = 0.021) and depression (p = 0.032), as compared to the patients without these co-morbidities. The minor allele T frequency of rs5751876 was lower in GTS patients with co-morbid attention deficit hyperactivity disorder (p = 0.022), and TT+TC genotypes were less frequent in the non-OCD anxiety disorder group (p = 0.045). Conclusion ADORA1 and ADORA2A variants are associated with the risk of GTS, co-morbid disorders, and may affect the age of tic onset.