Biology subjects

Matiasek, K.

Publications and source records attributed to Matiasek, K..

6 recordsLinked to original sources

bioRxiv2025

A missense variant in PAOX in American Staffordshire Terriers with juvenile-onset polyneuropathy

Hereditary polyneuropathies in dogs mirror many features of human Charcot-Marie-Tooth (CMT) disease and offer valuable spontaneous models for discovery of genes variants involved in this disorder. A juvenile-onset polyneuropathy (JOP) in American Staffordshire Terriers (ASTs) resembles CMT, with motor and sensory deficits, often accompanied by laryngeal paralysis. To identify the underlying genetic cause, we conducted a genome-wide association study (GWAS) with 24 affected and 53 control ASTs that identified a significant locus at the distal end of chromosome 28. Homozygosity mapping analysis further defined a critical interval spanning 11 protein-coding genes and whole-genome sequencing revealed a missense variant in the PAOX gene encoding polyamine oxidase (NC_049249.1:g.41474541G>A), leading to a glycine-to-arginine substitution at a highly conserved residue, XP_038435135.1:p.(Gly382Arg). Genotypes at this variant were homozygous alternate in 96% of the affected dogs (n=53) and either homozygous reference or heterozygous in 336 unaffected ASTs; the mutant allele was not detected in any of 2519 genomes of other dog breeds. In silico predictions consistently supported its pathogenicity, and structural modeling suggested altered substrate binding. Although PAOX expression was preserved, proteomic profiling in affected nerve tissue revealed reduced levels of myelin-associated proteins, as well as dysregulation of mitochondrial and proteasomal pathways. Our findings establish this PAOX missense variant as the likely cause of JOP in ASTs and highlight the breed as a valuable large-animal model for studying inherited peripheral neuropathies. These results expand the spectrum of genes implicated in polyneuropathies and provide a basis for genetic testing and informed breeding strategies in ASTs. Author summaryWe studied a hereditary peripheral nerve disorder in American Staffordshire Terriers characterized by exercise intolerance, coordination problems, general weakness and difficulty breathing due to laryngeal paralysis. These signs closely resemble a group of inherited diseases in people known as Charcot-Marie-Tooth disease. To understand the genetic basis of this condition in dogs, we analyzed the genomes of affected and healthy individuals. Our research led us to a single gene, PAOX, which carries a missense variant likely affecting the function of polyamine oxidase and ultimately disrupting how the nerve cells function and survive. Most affected dogs had two copies of the mutant allele, while it was absent or in only one copy in healthy dogs. Additional analyses suggested that the variant may interfere with the nerves ability to maintain their structure and function properly. The mutant allele does not appear to reduce the overall level of PAOX protein, but it may affect how the protein works. Our findings provide a new genetic test that can help breeders avoid producing affected puppies. They also highlight this condition in dogs as a valuable model for understanding similar diseases in humans.

genetics↗

bioRxiv2025

Borna disease virus 1 infection causing fatal meningoencephalomyelitis in wild European hedgehogs in known endemic areas, Germany, 2022 to 2024

Herein, we report Borna disease virus 1 (BoDV-1) infection in seven wild European hedgehogs (Erinaceus europaeus) from an endemic area in Germany. BoDV-1 causes encephalitis with a fatality rate of more than 90% in domestic mammals and humans. Currently, the bicolored white-toothed shrew (Crocidura leucodon) is the only known reservoir host. As hedgehogs are distant relatives of shrews and often cared for by humans, the cases raise concern regarding a potential zoonotic risk. All of the hedgehogs that tested positive for BoDV-1 had succumbed to neurological disease and exhibited severe polio-predominant lymphoplasmohistiocytic meningoencephalitis. However, due to the detection of viral antigens in non-neural cells in one animal, it cannot be completely excluded that some infected hedgehogs shed the virus. Although direct BoDV-1 transmission is known to be inefficient, our results emphasize the necessity of hygiene measures when handling hedgehogs, especially those with neurological signs from BoDV-1-endemic regions.

pathology↗

bioRxiv2025

Multi-modal analysis of satellite cells reveals early impairments at pre-contractile stages of myogenesis in Duchenne muscular dystrophy

Recent studies on the role of myogenic satellite cells (SC) in Duchenne muscular dystrophy (DMD) documented altered division capacities and impaired regeneration potential of SC in DMD patients and animal models. It remains unknown, however, if SC-intrinsic effects trigger these deficiencies at pre-contractile stages of myogenesis rather than resulting from the pathologic environment. Addressing this, we isolated SC from muscle biopsies of a porcine DMD model for characterization. Traction force microscopy (TFM) revealed that DMD SC produce a significantly higher strain energy than wild-type cells (WT; 0.136 {+/-} 0.016 {micro}J vs. 0.057 {+/-} 0.008 {micro}J). By RNA-seq, we identified 1,390 differentially expressed genes and proteomics measurements detected 1,261 proteins with altered abundance in DMD vs. WT. Dysregulated pathways uncovered by Gene Ontology (GO) enrichment analysis included sarcomere organization, focal adhesion, and response to hypoxia. We integrated the data using multi-omics factor analysis (MOFA) and identified five factors accounting for the variance with an overall higher contribution of the transcriptomic (61.95 %) than the proteomic data (54.02 %). Our findings suggest SC impairments result from their inherent genetic abnormality rather than environmental influences. The observed biological changes are independent and not reactive to the pathological surrounding of DMD muscle.

pathology↗

bioRxiv2023

Multimodally trackable and clinically translatable platform for modelling human demyelinating brain diseases by temporally dispersed chemically induced lesions in thepig brain

BackgroundDespite advances in therapy, inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, remain important causes of morbidity among young adults. Translation of remyelinating paradigms from current murine models is encumbered by the small size and low white matter content of the brains, limiting the spatial resolution of diagnostic imaging. Large animal models might be more suited for this purpose but pose significant technological, ethical and logistical challenges. MethodWe induced reversible and targeted cerebral demyelinating lesions by controlled injection of lysophosphatidylcholine in the minipig brain. One strength of the approach is the serial induction, allowing parallel imaging of successive stages of de-/remyelination. FindingsWe demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics, as well as electron microscopy to compare against biopsy data from two patients with cerebral demyelination. InterpretationBy employing human diagnostic tools and validating the model against data from related human diseases, our platform overcomes one important translational barrier of current animal brain demyelination models while having the potential for developing diagnostic procedures and imaging biomarkers. Remyelination and axon preservation dynamics diverge from classical rodent models. FundingThis work was supported by the DFG under Germanys Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSInflammatory demyelinating diseases of the central nervous system (CNS), targeting primarily the white matter (WM) of the brain and spinal cord, such as multiple sclerosis (MS), still represent some of the most important non-traumatic causes of disability in young adults. Current animal models based on murine species, for example, experimental autoimmune encephalomyelitis, have been demonstrated to reliably depict pathophysiological facets of human disease. However, they are nevertheless encumbered by the low WM content and the small size of murine brains, which still pose a translational barrier to diagnostic imaging tools used in a clinical context in human patients. Minipigs are increasingly being used to model human neurological diseases, as yet primarily in the context of neurodegenerative disorders. Added value of this studyHere, we establish a platform for Minipig Stereotactic White-matter Injection using Navigation by Electromagnetism (MiniSWINE) and validate such a tool in a clinical multimodal imaging and microscopy setting against biopsy and imaging data from human demyelinating disorders across different disease stages, as well as against existing and potentially emerging human diagnostic imaging. Moreover, in order to overcome the neuroanatomical challenges of stereotactic injection in the pig brain, we designed a new electromagnetic-guided tracking system whose key advantage is the direct measurement of the injection cannula tip position in situ. Another strength of our study lies in its setup, characterized by the serial induction of successive stages of de- and remyelination, allowing for multimodal assessment via imaging and histopathology or electron microscopy of multiple stages in parallel. The remyelination dynamics inferred in this context diverge from the classical rodent studies, by exhibiting incomplete remyelination at the subacute stage, persistent astroglial and microglial activation as well as a minor degree of secondary axonal degeneration. Thus, they more closely resemble human inflammatory demyelinating brain plaques. Implications of all the available evidenceWe believe that MiniSWINE links evidence from well-established demyelination-induction methods from rodent models of CNS demyelinating disorders, as well as from human imaging and biopsy data, while at the same time providing a novel platform for the potential development of diagnostic procedures, discovery of imaging biomarkers and testing of remyelinating agents in diseases such as MS. Thus, it can have particular relevance to human health in the context of future translational animal model-based research in inflammatory demyelinating disorders of the CNS. Additionally, our electromagnetic-guided injection technique may enhance stereotactic substance delivery in human neurosurgery.

neuroscience↗

bioRxiv2022

Mystery of fatal "Staggering disease" unravelled: Novel rustrela virus causes severe encephalomyelitis in domestic cats

Staggering disease is a neurological disorder considered a threat to European domestic cats (Felis catus) for almost five decades. However, its aetiology has remained obscure. Rustrela virus (RusV), a relative of rubella virus, has recently been shown to be associated with encephalitis in a broad range of mammalian hosts. Here, we report the detection of RusV RNA and antigen by metagenomic sequencing, RT-qPCR, in-situ hybridization and immunohistochemistry in brain tissues of 28 out of 29 cats with non-suppurative meningoencephalomyelitis and staggering disease-like neurological disorder from Sweden, Austria, and Germany, but not in non-affected control cats. Screening of possible reservoir hosts in Sweden revealed RusV infection in wood mice (Apodemus sylvaticus). Our work strongly indicates RusV as the long-sought cause of feline staggering disease. Given its broad host spectrum and considerable geographic range, RusV may be the aetiological agent of neuropathologies in further mammals, possibly even including humans.

microbiology↗

bioRxiv2021

A scalable, clinically severe pig model for Duchenne muscular dystrophy

Large animal models for Duchenne muscular dystrophy (DMD) are crucial for preclinical evaluation of novel diagnostic procedures and treatment strategies. Pigs cloned from male cells lacking DMD exon 52 (DMD{Delta}52) resemble molecular, clinical and pathological hallmarks of DMD, but cannot be propagated by breeding due to death before sexual maturity. Therefore, female DMD+/- carriers were generated. A single founder animal had 11 litters with 29 DMDY/-, 34 DMD+/- as well as 36 male and 29 female wild-type (WT) offspring. Breeding with F1 and F2 DMD+/- carriers resulted in additional 114 DMDY/- piglets. The majority of them survived for 3-4 months, providing large cohorts for experimental studies. Pathological investigations and proteome studies of skeletal muscles and myocardium confirmed the resemblance of human disease mechanisms. Importantly, DMDY/- pigs reveal progressive fibrosis of myocardium and increased expression of connexin-43, associated with significantly reduced left ventricular fractional shortening and ejection fraction already at age 3 months. Furthermore, behavioral tests provided evidence for impaired cognitive ability of DMDY/- pigs. Our breeding cohort of DMD{Delta}52 pigs and standardized tissue repositories from DMDY/- pigs, DMD+/- carriers, and WT littermate controls provide important resources for studying DMD disease mechanisms and for testing novel diagnostic procedures and treatment strategies.

pathology↗