INTRODUCTION: Corticobasal syndrome (CBS) is a specific clinical manifestation shared by multiple pathologies. The exact mechanism of this phenomenon remains unclear. Differential diagnosis of CBS in everyday clinical practice is challenging, as this syndrome can overlap with other entities, especially progressive supranuclear palsy Richardson-Steele phenotype (PSP-RS). Several papers have suggested a possible role of vascular pathology as a linking factor in the pathogenesis of CBS based on different neuropathologies. This paper analyses differences in the occurrence of the most common vascular risk factors such as hypertension and lipid profile with respect to dietary habits among patients who fulfill the diagnostic criteria for probable/possible CBS and PSP-RS. MATERIAL AND METHODS: Seventy (70) patients in total were included in the study. Exclusion criteria comprised hydrocephalus, stroke in the past, the presence of marked vascular changes in white matter defined as the presence of vascular change ≥ 1 mm in 3T MRI, medical history of hyperlipidemia or the use of drugs that could impact upon lipid metabolism before the initiation of the neurodegenerative disease, and neoplastic focuses in the central nervous system. Patients with diabetes, or with BMI exceeding 18-25, or who were smokers, or who were affected by chronic stress were also excluded. Data was analysed statistically using the Shapiro-Wilk test, the U Mann-Whitney test for group comparison, and a Bonferroni correction to control the false discovery rate (FDR). RESULTS: Our obtained results indicated a statistically significantly higher level of total cholesterol in the CBS group (p = 0.0039) without a correlation with dietary habits. CONCLUSIONS AND CLINICAL IMPLICATIONS: The results obtained in our study may suggest a possible role of vascular pathology in CBS development. This issue requires further research.

• Klíčová slova
• CBS phenotype, corticobasal syndrome, hyperlipidemia, neurodegeneration, risk factor,
• MeSH
• hyperlipidemie * MeSH
• kortikobazální degenerace * MeSH
• lidé MeSH
• neurodegenerativní nemoci * etiologie   diagnóza   patologie   MeSH
• pilotní projekty MeSH
• progresivní supranukleární obrna * diagnóza   patologie   MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Objective: Alzheimer's disease (AD) is the most common neurodegenerative disease. The predominantly sporadic form of AD is age-related, but the underlying pathogenic mechanisms remain not fully understood. Current efforts to combat the disease focus on the main pathological hallmarks, in particular beta-amyloid (Aβ) plaque pathology. According to the amyloid cascade hypothesis, Aβ is the critical early initiator of AD pathogenesis. Plaque pathology is very heterogeneous, where a subset of plaques, neuritic plaques (NPs), are considered most neurotoxic rendering their in-depth characterization essential to understand Aβ pathogenicity. Methods: To delineate the chemical traits specific to NP types, we investigated senile Aβ pathology in the postmortem, human sporadic AD brain using advanced correlative biochemical imaging based on immunofluorescence (IF) microscopy and mass spectrometry imaging (MSI). Results: Immunostaining-guided MSI identified distinct Aβ signatures of NPs characterized by increased Aβ1-42(ox) and Aβ2-42. Moreover, correlation with a marker of dystrophy (reticulon 3 [RTN3]) identified key Aβ species that both delineate NPs and display association with neuritic dystrophy. Conclusion: Together, these correlative imaging data shed light on the complex biochemical architecture of NPs and associated dystrophic neurites. These in turn are obvious targets for disease-modifying treatment strategies, as well as novel biomarkers of Aβ pathogenicity.

• Klíčová slova
• Alzheimer's disease, beta-amyloid, cored plaques, dystrophic neuritis, matrix-assisted laser/desorption ionization mass spectrometry imaging, neuritic plaques,
• MeSH
• Alzheimerova nemoc * diagnostické zobrazování   patologie   MeSH
• amyloidní beta-protein chemie   metabolismus   MeSH
• amyloidní plaky diagnostické zobrazování   patologie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mozek patologie   MeSH
• myši transgenní MeSH
• myši MeSH
• neurodegenerativní nemoci * patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloidní beta-protein MeSH

Huntington´s disease (HD) is a progressive neurodegenerative disease with onset in adulthood that leads to a complete disability and death in approximately 20 years after onset of symptoms. HD is caused by an expansion of a CAG triplet in the gene for huntingtin. Although the disease causes most damage to striatal neurons, other parts of the nervous system and many peripheral tissues are also markedly affected. Besides huntingtin malfunction, mitochondrial impairment has been previously described as an important player in HD. This study focuses on mitochondrial structure and function in cultivated skin fibroblasts from 10 HD patients to demonstrate mitochondrial impairment in extra-neuronal tissue. Mitochondrial structure, mitochondrial fission, and cristae organization were significantly disrupted and signs of elevated apoptosis were found. In accordance with structural changes, we also found indicators of functional alteration of mitochondria. Mitochondrial disturbances presented in fibroblasts from HD patients confirm that the energy metabolism damage in HD is not localized only to the central nervous system, but also may play role in the pathogenesis of HD in peripheral tissues. Skin fibroblasts can thus serve as a suitable cellular model to make insight into HD pathobiochemical processes and for the identification of possible targets for new therapies.

• Klíčová slova
• Huntington’s disease, fibroblasts, mitochondrial dysfunction, mitochondrial network, oxidative phosphorylation system, ultrastructure,
• MeSH
• dospělí MeSH
• fibroblasty metabolismus   MeSH
• Huntingtonova nemoc * genetika   metabolismus   patologie   MeSH
• lidé MeSH
• mitochondrie patologie   MeSH
• neurodegenerativní nemoci * metabolismus   patologie   MeSH
• neurony patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson's disease, Friedreich's disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood-brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

• Klíčová slova
• MRI, NBIA, chelation, ferroptosis, iron accumulation, neurodegeneration, siderosis,
• MeSH
• lidé MeSH
• mozek patologie   MeSH
• neuroaxonální dystrofie * patologie   MeSH
• neurodegenerativní nemoci * patologie   MeSH
• poruchy metabolismu železa * patologie   MeSH
• železo farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• železo MeSH

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) are a group of clinically and genetically heterogeneous diseases characterized by iron overload in basal ganglia and progressive neurodegeneration. Little is known about the epidemiology of NBIA disorders. In the absence of large-scale population-based studies, obtaining reliable epidemiological data requires innovative approaches. METHODS: All pathogenic variants were collected from the 13 genes associated with autosomal recessive NBIA (PLA2G6, PANK2, COASY, ATP13A2, CP, AP4M1, FA2H, CRAT, SCP2, C19orf12, DCAF17, GTPBP2, REPS1). The allele frequencies of these disease-causing variants were assessed in exome/genome collections: the Genome Aggregation Database (gnomAD) and our in-house database. Lifetime risks were calculated from the sum of allele frequencies in the respective genes under assumption of Hardy-Weinberg equilibrium. FINDINGS: The combined estimated lifetime risk of all 13 investigated NBIA disorders is 0.88 (95% confidence interval 0.70-1.10) per 100,000 based on the global gnomAD dataset (n = 282,912 alleles), 0.92 (0.65-1.29) per 100,000 in the European gnomAD dataset (n = 129,206), and 0.90 (0.48-1.62) per 100,000 in our in-house database (n = 44,324). Individually, the highest lifetime risks (>0.15 per 100,000) are found for disorders caused by variants in PLA2G6, PANK2 and COASY. INTERPRETATION: This population-genetic estimation on lifetime risks of recessive NBIA disorders reveals frequencies far exceeding previous population-based numbers. Importantly, our approach represents lifetime risks from conception, thus including prenatal deaths. Understanding the true lifetime risk of NBIA disorders is important in estimating disease burden, allocating resources and targeting specific interventions. FUNDING: This work was carried out in the framework of TIRCON ("Treat Iron-Related Childhood-Onset Neurodegeneration").

• Klíčová slova
• Autosomal recessive NBIA disorders, CoPAN, Lifetime risk, Neurodegeneration, PKAN, PLAN,
• MeSH
• databáze genetické MeSH
• dítě MeSH
• jaderné proteiny MeSH
• komplexy ubikvitinligas MeSH
• lidé MeSH
• mitochondriální proteiny genetika   MeSH
• mozek patologie   MeSH
• neuroaxonální dystrofie * epidemiologie   genetika   patologie   MeSH
• neurodegenerativní nemoci * epidemiologie   genetika   patologie   MeSH
• poruchy metabolismu železa * genetika   patologie   MeSH
• proteiny vázající vápník MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• C19orf12 protein, human MeSH Prohlížeč
• DCAF17 protein, human MeSH Prohlížeč
• jaderné proteiny MeSH
• komplexy ubikvitinligas MeSH
• mitochondriální proteiny MeSH
• proteiny vázající vápník MeSH
• REPS1 protein, human MeSH Prohlížeč

The exact signaling leading to neurological dysfunction in neurodegenerative diseases is currently unknown. We hypothesize that the c-Jun N-terminal kinase (JNK) signaling pathway is a potential therapeutic target for neurodegenerative diseases. This postulate rests on extensive data from cell and animal experimental studies, demonstrating that JNK signaling plays a crucial role in the pathogenesis of neurodegenerative diseases. The sustained activation of JNK leads to synaptic dysfunction and even neuronal apoptosis, ultimately resulting in memory deficits and neurodegeneration. JNK phosphorylates the amyloid precursor protein and tau, ultimately resulting in the formation of extraneuronal senile plaques and intraneuronal neurofibrillary tangles. Our hypothesis could be validated by investigating the cerebral cortex of elderly chimpanzees injected with phosphorylated JNK or transgenic pig and chimpanzee models established using gene editing technology including CRISPR. This hypothesis provides clues for further understanding the molecular mechanisms of neurodegenerative diseases and the development of potential target therapeutic drugs.

• Klíčová slova
• Alzheimer's disease, JNK, amyloid beta, neurodegenerative diseases, tau,
• MeSH
• Alzheimerova nemoc genetika   MeSH
• amyloidní beta-protein * metabolismus   MeSH
• amyloidový prekurzorový protein beta * genetika   metabolismus   MeSH
• fosforylace MeSH
• genový targeting * MeSH
• JNK mitogenem aktivované proteinkinasy metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mozková kůra metabolismus   patologie   MeSH
• neurodegenerativní nemoci patologie   MeSH
• neurony metabolismus   MeSH
• Pan troglodytes MeSH
• prasata MeSH
• proteiny tau metabolismus   MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• amyloidní beta-protein * MeSH
• amyloidový prekurzorový protein beta * MeSH
• JNK mitogenem aktivované proteinkinasy MeSH
• proteiny tau MeSH

Tunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection. Additionally, TNTs contribute to acquiring resistance to cancer therapy, probably via their ability to rescue cells by ameliorating various pathological stresses, such as oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, and apoptotic stress. Moreover, mesenchymal stem cells play a crucial role in the rejuvenation of targeted cells with mitochondrial heteroplasmy and oxidative stress by transferring healthy mitochondria through TNTs. Recent research has focussed on uncovering the key regulatory molecules involved in the biogenesis of TNTs. However further work will be required to provide detailed understanding of TNT regulation. In this review, we discuss possible associations with Rho GTPases linked to oxidative stress and apoptotic signals in biogenesis pathways of TNTs and summarize how intercellular trafficking of cargo and organelles, including mitochondria, via TNTs plays a crucial role in disease progression and also in rejuvenation/therapy.

• Klíčová slova
• Apoptosis, Cellular stress, Chemotherapy resistance, Intercellular transfer, Mesenchymal stem cells, Mitochondrial homeostasis, Reactive oxygen species (ROS), Rejuvenation,
• MeSH
• lidé MeSH
• mezibuněčná komunikace * MeSH
• mitochondrie metabolismus   MeSH
• nádory metabolismus   patologie   MeSH
• neurodegenerativní nemoci metabolismus   patologie   MeSH
• organely metabolismus   MeSH
• oxidační stres * MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• rho proteiny vázající GTP fyziologie   MeSH
• virové nemoci metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• reaktivní formy kyslíku MeSH
• rho proteiny vázající GTP MeSH

Cholinesterases are fundamental players in the peripheral and central nervous systems [...].

• MeSH
• acetylcholinesterasa genetika   metabolismus   MeSH
• butyrylcholinesterasa genetika   metabolismus   MeSH
• centrální nervový systém cytologie   účinky léků   enzymologie   MeSH
• cholinesterasové inhibitory terapeutické užití   MeSH
• exprese genu MeSH
• GPI-vázané proteiny genetika   metabolismus   MeSH
• lidé MeSH
• nervový přenos MeSH
• neurodegenerativní nemoci farmakoterapie   enzymologie   genetika   patologie   MeSH
• neurony cytologie   účinky léků   enzymologie   MeSH
• neuroprotektivní látky terapeutické užití   MeSH
• periferní nervový systém cytologie   účinky léků   enzymologie   MeSH
• synapse účinky léků   enzymologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• úvodníky MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• ACHE protein, human MeSH Prohlížeč
• BCHE protein, human MeSH Prohlížeč
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• GPI-vázané proteiny MeSH
• neuroprotektivní látky MeSH

Numerous pathological changes of subcellular structures are characteristic hallmarks of neurodegeneration. The main research has focused to mitochondria, endoplasmic reticulum, Golgi apparatus, lysosomal networks as well as microtubular system of the cell. The sequence of specific organelle damage during pathogenesis has not been answered yet. Exposition to rotenone is used for simulation of neurodegenerative changes in SH-SY5Y cells, which are widely used for in vitro modelling of Parkinson´s disease pathogenesis. Intracellular effects were investigated in time points from 0 to 24 h by confocal microscopy and biochemical analyses. Analysis of fluorescent images identified the sensitivity of organelles towards rotenone in this order: microtubular cytoskeleton, mitochondrial network, endoplasmic reticulum, Golgi apparatus and lysosomal network. All observed morphological changes of intracellular compartments were identified before alphaS protein accumulation. Therefore, their potential as an early diagnostic marker is of interest. Understanding of subcellular sensitivity in initial stages of neurodegeneration is crucial for designing new approaches and a management of neurodegenerative disorders.

• MeSH
• apoptóza MeSH
• insekticidy toxicita   MeSH
• lidé MeSH
• mikrotubuly účinky léků   metabolismus   patologie   MeSH
• mitochondrie účinky léků   metabolismus   patologie   MeSH
• nádorové buněčné linie MeSH
• NADPH-oxidasy metabolismus   MeSH
• neuroblastom komplikace   MeSH
• neurodegenerativní nemoci etiologie   metabolismus   patologie   MeSH
• rotenon toxicita   MeSH
• viabilita buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• insekticidy MeSH
• NADPH-oxidasy MeSH
• rotenon MeSH

Exercise therapy represents an important tool for the treatment of many neurological diseases, including cerebellar degenerations. In mouse models, exercise may decelerate the progression of gradual cerebellar degeneration via potent activation of neuroprotective pathways. However, whether exercise could also improve the condition in mice with already heavily damaged cerebella remains an open question. Here we aimed to explore this possibility, employing a mouse model with dramatic early-onset cerebellar degeneration, the Lurcher mice. The potential of forced physical activity and environmental enrichment (with the possibility of voluntary running) for improvement of behaviour and neuroplasticity was evaluated by a series of behavioural tests, measuring BDNF levels and using stereological histology techniques. Using advanced statistical analysis, we showed that while forced physical activity improved motor learning by ∼26 % in Lurcher mice and boosted BDNF levels in the diseased cerebellum by 57 %, an enriched environment partially alleviated some behavioural deficits related to behavioural disinhibition. Specifically, Lurcher mice exposed to the enriched environment evinced reduced open arm exploration in elevated plus maze test by 18 % and increased immobility almost 9-fold in the forced swim test. However, we must conclude that the overall beneficial effects were very mild and much less clear, compared to previously demonstrated effects in slowly-progressing cerebellar degenerations.

• Klíčová slova
• Behaviour, Cerebellar degeneration, Enriched environment, Forced physical activity, Lurcher mouse, motor functions,
• MeSH
• bydlení zvířat * MeSH
• chování zvířat fyziologie   MeSH
• hra a hračky MeSH
• kondiční příprava zvířat fyziologie   MeSH
• modely nemocí na zvířatech MeSH
• mozeček * metabolismus   patologie   MeSH
• mozkový neurotrofický faktor metabolismus   MeSH
• myši - mutanty neurologické MeSH
• myši MeSH
• neurodegenerativní nemoci * metabolismus   patologie   rehabilitace   MeSH
• terapie cvičením MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Bdnf protein, mouse MeSH Prohlížeč
• mozkový neurotrofický faktor MeSH