Markus Tolnay

• Universitätsspital Basel

DNA methylation analysis based on supervised machine learning algorithms with static reference data, allowing diagnostic tumour typing with unprecedented precision, has quickly become a new standard of care. Whereas genome-wide diagnostic methylation profiling is mostly performed on microarrays, an increasing number of institutions additionally emp...

Precision medicine is entering a new era of digital diagnostics; the availability of integrated digital pathology (DP) and structured clinical datasets has the potential to become a key catalyst for biomedical research, education and business development. In Europe, national programs for sharing of this data will be crucial for the development, tes...

Abnormal tau protein aggregates constitute a hallmark of Alzheimer's disease. The mechanisms underlying the initiation of tau aggregation in sporadic neurodegeneration remain unclear. Here we investigate whether a non-human prion can seed tau aggregation. Due to their structural similarity with tau aggregates, we chose Sup35NM yeast prion domain fi...

Risk stratification of COVID-19 patients is essential for pandemic management. Changes in the cell fitness marker, hFwe-Lose, can precede the host immune response to infection, potentially making such a biomarker an earlier triage tool. Here, we evaluate whether hFwe-Lose gene expression can outperform conventional methods in predicting outcomes (e...

Tau is a microtubule stabilizing protein that forms abnormal aggregates in many neurodegenerative disorders, including Alzheimer’s disease. We have previously shown that co-expression of fragmented and full-length tau in P301SxTAU62on tau transgenic mice results in the formation of oligomeric tau species and causes severe paralysis. This paralysis...

The application and integration of molecular profiling technologies create novel opportunities for personalized medicine. Here, we introduce the Tumor Profiler Study, an observational trial combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making with an exploratory approach...

Motivation Recent technological advances have led to an increase in the production and availability of single-cell data. The ability to integrate a set of multi-technology measurements would allow the identification of biologically or clinically meaningful observations through the unification of the perspectives afforded by each technology. In most...

Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Here w...

Objectives: Tumor mutational burden (TMB) has emerged as a promising predictive biomarker for immune checkpoint inhibitor therapy. While the feasibility of TMB analysis on formalin-fixed paraffin-embedded (FFPE) samples has been thoroughly evaluated, only limited analyses have been performed on cytological samples, and no dedicated study has inves...

The pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder, is complex and involves the impairment of crucial intracellular physiological processes. Importantly, in addition to abnormal α-synuclein aggregation, the dysfunction of various mitochondria-dependent processes has been prominently implicated in PD path...

Granulovacuolar degeneration bodies (GVBs) are membrane-bound vacuolar structures harboring a dense core that accumulate in the brains of patients with neurodegenerative disorders, including Alzheimer’s disease and other tauopathies. Insight into the origin of GVBs and their connection to tau pathology has been limited by the lack of suitable exper...

Tau is a microtubule stabilizing protein that forms aggregates in Alzheimer’s disease (AD). Tau derived from AD patients’ brains induces tau aggregation in a prion-like manner when injected into susceptible mouse models. Here we investigated whether cerebrospinal fluid (CSF) collected from patients diagnosed with probable AD or mild cognitive impai...

Synoptic reporting (SR) increases completeness and improves the understanding of pathology reports for tumours as compared to the more traditional “narrative” style. Furthermore, it is an important step towards higher levels of structured data capture [1]. SR is defined by a set of required data elements (RDE) specific for each tumour type and a ch...

Stress adaptation is essential for neuronal health. While the fundamental role of mitochondria in neuronal development has been demonstrated, it is still not clear how adult neurons respond to alterations in mitochondrial function and how neurons sense, signal, and respond to dysfunction of mitochondria and their interacting organelles. Here, we sh...

Examination of tumor molecular characteristics by liquid biopsy is likely to greatly influence personalized cancer patient management. Analysis of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and tumor-derived exosomes, all collectively referred to as “liquid biopsies,” are not only a modality to monitor treatment efficacy, diseas...

Background/aims: Cerebral small vessel disease (SVD) is characterized by periventricular white matter (WM) changes and can lead to vascular dementia, the second most common form of age-dependent dementia. The pathogenesis of the disease remains poorly understood, and studies of its molecular basis are limited. By profiling gene expression of disse...

Tauopathies constitute neurodegenerative diseases that are characterized by the intracellular deposition of filaments made of hyperphosphorylated tau protein. The pattern of tau deposition in Alzheimer's disease follows a stereotypical progression, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where they appear...

We report two cases of unclear granulomatous encephalitis where pathogenic algae, genus Prototheca, were identified as causative agent. Granulomatous encephalitis is - after exclusion of cause - per definition diagnosed and managed as neurosarcoidosis. However, protothecal infections go undetected by standard bacterial and fungal rDNA screening. As...

During apoptosis mitochondria undergo cristae remodeling and fragmentation, but how the latter relates to outer membrane permeabilization and downstream caspases activation is unclear. Here we show that the mitochondrial fission protein Dynamin Related Protein (Drp) 1 participates in cytochrome c release by selected intrinsic death stimuli. While B...

Abundant tau inclusions are a defining hallmark of several human neurodegenerative diseases, including Alzheimer's disease. Protein fragmentation is a widely observed event in neurodegenerative proteinopathies. The relevance of tau fragmentation for the neurodegenerative process in tauopathies has yet remained unclear. Here we found that co-express...

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathob...

Cerebral small-vessel disease (SVD) is characterized by periventricular white matter (WM) changes and general brain atrophy. SVD is prevalent in elderly individuals and is frequently associated with the development of vascular dementia (VaD). Studies of the molecular basis of SVD are sparse. We have to gain further insight into the pathogenic mecha...

Early diagnosis of Alzheimer`s disease (AD) is currently difficult and involves a complex approach including clinical assessment, neuroimaging, and measurement of amyloid-β (Aβ) and tau levels in cerebrospinal fluid (CSF). A better mechanistic understanding is needed to develop more accurate and even presymptomatic diagnostic tools. It has been sho...

Early diagnosis of Alzheimer`s disease (AD) iscurrently difficult and involves acomplex approach including clinical assessment, neuroimaging, and measurement of amyloid-β (Aβ) and tau levelsin cerebrospinal fluid (CSF). A better mechanistic understanding is needed to develop more accurate and even presymptomatic diagnostic tools. It has been shown...

Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that...

It has been proposed that tau aggregation confined to entorhinal cortex and hippocampus, with no or only minimal Aβ deposition, should be considered as a 'primary age-related tauopathy' (PART) that is not integral to the continuum of sporadic Alzheimer disease (AD). Here, we examine the evidence that PART has a pathogenic mechanism and a prognosis...

Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by the abnormal aggregation of a small number of intracellular proteins, with tau and α-synuclein being the most commonly affected. Until recently, the events leading to aggregate formation were believed to be entirely cell-autonomous, with protein...

Filaments made of hyperphosphorylated tau protein are encountered in a number of neurodegenerative diseases referred to as “tauopathies”. In the most prevalent tauopathy, Alzheimer's disease, tau pathology progresses in a stereotypical manner with the first lesions appearing in the locus coeruleus and the entorhinal cortex from where they appear to...

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3′–5′ DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here...

Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer’s disease, progressive supranuclear palsy, Pick’s disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spre...

Filaments made of hyperphosphorylated tau protein are encountered in a group of neurodegenerative disorders termed tauopathies. The most prevalent tauopathy, Alzheimer's disease (AD), additionally presents with extracellular deposits of the amyloid-β peptide (Aβ). Current symptomatic treatments have shown short term benefits in reducing cognitive s...

Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer's disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer's disease and AGD, it has been shown that filamentous...

Altered autophagy contributes to the pathogenesis of Alzheimer's disease and other tauopathies, for which curative treatment options are still lacking. We have recently shown that trehalose reduces tau pathology in a tauopathy mouse model by stimulation of autophagy. Here, we studied the effect of the autophagy inducing drug rapamycin on the progre...

Intraperitoneal rapamycin administration resulted in high cerebral rapamycin levels as measured by HPLC. Similar levels were achieved in the forebrain and the brain stem (A; B6 1.5 WT; FB = forebrain, BS: brain stem, BL: blood). Consistent with cerebral mTOR inhibition, Western blotting of forebrain tissue showed significantly reduced phosphorylati...

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Forebrain levels of soluble tau protein remained unchanged after both, 5 months or 6 weeks of rapamycin treatment (A; 5 MT, p = 0.35; 6 WT, p = 0.18). We also analyzed the immediate effects of a short rapamycin treatment of 1.5 weeks duration on forebrain tau levels in pretangle P301S mice. There again was no reduction of soluble tau by rapamycin t...

For the qualitative assessment of astrogliosis in long-term rapamycin treated mice, blinded sets comprising every 5th 20 µm section of 5MT mice were rated from – (A), + (B), ++ (C) to +++ (D) by three independent raters (S.O., K.B., D.W.). The median rating of the GFAP stainings of all sections was listed per brain region and mouse for a qualitativ...

Scheme of the study indicating the treatment schedules of the different groups of rapamycin (R) or vehicle (V) treated P301S mutant tau transgenic mice and non-transgenic C57BL/6J mice. P301S mice were treated twice weekly intraperitoneally with 15 mg rapamycin per kg body weight or vehicle from 3 weeks to 5.5 months of age (group 5-months treatmen...

The soluble microtubule-associated protein tau forms hyperphosphorylated, insoluble and filamentous inclusions in a number of neurodegenerative diseases referred to as "tauopathies." In Alzheimer's disease, tau pathology develops in a stereotypical manner, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where the...

Personalised medicine is an emerging model that will revolutionise our current healthcare system. In the last decade, several genomic aberrations were discovered that are now used as predictive markers for treatment with targeted therapeutics. The technological advances in the last few years, such as the development of high resolution DNA microarra...

The accumulation of insoluble proteins is a pathological hallmark of several neurodegenerative disorders. Tauopathies are caused by the dysfunction and aggregation of tau protein and an impairment of cellular protein degradation pathways may contribute to their pathogenesis. Thus, a deficiency in autophagy can cause neurodegeneration, while activat...

Neurodegenerative tauopathies may be inherited as autosomal-dominant disorders with variable clinicopathological phenotypes, and causative mutations in the microtubule-associated protein tau (MAPT) gene are not regularly seen. Herein, we describe a patient with clinically typical and autopsy-proven corticobasal degeneration (CBD). Her mother was di...

Nach einer Darstellung der funktionellen Anatomie von Stammganglien und Kleinhirn werden Pathologie, Genetik und Klinik von Krankheiten mit Degeneration der Motoneurone (amyotrophe Lateralsklerose, spinale Muskelatrophie), Krankheiten mit Ataxie (Friedreich-Krankheit, spinozerebelläre Ataxien, DRPLA), Krankheiten mit Chorea (Huntington-Krankheit un...

Changes in optical density from ETC enzymatic activities depends on incubation time. Changes in optical density (OD) plotted over time, after extraction from video recordings of the enzymatic staining for (A) NADH, (B) SDH and (C) COX activity at 20°C. The large difference between reaction times is due to the different incubation times necessary un...

Triacylglyceride levels in age-synchronized and mixed-age cultures of N2 and daf-2(e1370). Triacylglyceride level was measured by thin-layer chromatography in either synchronized cultures at day 1 of adulthood or mixed-age populations. Bars represent the standard error of the mean. Asterisks indicate statistical significance in comparison to wild t...

Comparison of three different methods for Oil-Red-O staining of neutral fat in C. elegans in whole animals. (A) Whole-mount permeabilized and Oil-Red-O stained animals on day 1 of adulthood. Note that lpd-3(ok2138) animals are thinner than wild type. Staining intensity is not obviously reduced. Blurring results from lipid droplets in various focal...

Full-resolution images of frozen and plastic-embedded sections of wild type animals, treated with various staining protocols. 1. Transversal sections through the mid-body; 2. Diagonal sections through the mid-body; 3. Transversal sections through the head. Staining methods: H&E, toluidine-blue (TOL, plastic), para-phenylene-diamine (PAR, plastic),...

Fresh frozen C. elegans sections stained with Oil-Red-O. Higher resolution images from Figure 4. (PDF)

The majority of metabolic principles are evolutionarily conserved from nematodes to humans. Caenorhabditis elegans has widely accelerated the discovery of new genes important to maintain organismic metabolic homeostasis. Various methods exist to assess the metabolic state in worms, yet they often require large animal numbers and tend to be performe...

Argyrophilic grain disease is a late-onset dementia morphologically characterized by abundant spindle-shaped argyrophilic grains in neuronal processes and coiled bodies in oligodendrocytes. Both lesions consist of the microtubule-associated protein tau in an abnormally hyperphosphorylated state and are predominantly composed of the four-repeat tau...

The soluble microtubule-associated protein tau becomes hyperphosphorylated, insoluble and filamentous in a number of neurodegenerative diseases collectively referred to as tauopathies. In Alzheimer’s disease (AD), tau pathology develops in a stereotypical manner, with the first lesions appearing in the locus coeruleus and the transentorhinal cortex...

Protease-resistant prion protein (PrP(Sc) ) is diagnostic of prion disease, yet its detection is frequently difficult. Here, we describe a patient with a PRNP P105T mutation and typical familial prion disease. Brain PrP(Sc) was undetectable by conventional Western blotting and barely detectable after phosphotungstate precipitation, where it display...

Background: Small fibre neuropathy is a sensory neuropathy affecting small, thinly myelinated Ad-fibres and unmyelinated C-fibres. It clinically presents with burning pain and sensory symptoms. As nerve conduction studies mainly detect large fibre function, they often show normal values. Skin biopsy is a new, minimally invasive and painless tool fo...

Secondary malignancies are infrequent sequelae of pituitary radiotherapy. The goal of the present case study is to analyze clinical features of a selected group of cases to define the special characteristics of these tumors. We report the illustrative case of a 38-year-old man with acromegaly who had transsphenoidal surgery and radiotherapy 7 years...

To investigate molecular mechanisms of peripheral nerve vasculitis, gene expression patterns in archived frozen sural nerve biopsies from patients with vasculitic neuropathy were compared to control nerves by DNA microarray technology. There was a striking upregulation of mRNA of genes involved in immune system processes. Of special interest was th...

The most common neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by the misfolding of a small number of proteins that assemble into ordered aggregates in affected brain cells. For many years, the events leading to aggregate formation were believed to be entirely cell-autonomous, with protein misfo...

GABA receptors are ubiquitous in the cerebral cortex and play a major role in shaping responses of cortical neurons. GABA(A) and GABA(B) receptor subunit expression was visualized by immunohistochemistry in human auditory areas from both hemispheres in 9 normal subjects (aged 43-85 years; time between death and fixation 6-24 hours) and in 4 stroke...

Chronic, daytime sleepiness is a major, disabling symptom for many patients with traumatic brain injury (TBI), but thus far, its etiology is not well understood. Extensive loss of the hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (orexin) causes the severe sleepiness of narcolepsy, and partial loss of these cells may...

Characterization of transgenic mice (A) Gene copy numbers per haploid genome in transgenic lines as determined by genomic Q-PCR. (B) relative mRNA level in brain extracts of transgenes compared to PrP mRNA in C57BL/6 mice (filled black columns and left y-axis) and compared Dpl mRNA in PrnpNgsk/Ngsk mice (open columns and right y-axis) using either...

Characterization of membrane anchored and PI-PLC treated transgenic proteins. Density gradient DRM preparations of wild-type, PrP GPI anchorless (PrPs), PrPΔCD and PrPΔCDs transgenic brains analyzed after PI-PLC treatment and deglycosylation with PNGase F with monoclonal antibody POM1. After PI-PLC treatment PrP and PrPΔCD had similarly buoyancy li...

Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease. In the disease process, neuronal tau inclusions first appear in the transentorhinal cortex from where they seem to spread to the hippocampal formation and neocortex. Cognitive impairment becomes manifest wh...