Histotype-Dependent Oligodendroglial PrP Pathology in Sporadic CJD: A Frequent Feature of the M2C “Strain”

Gelpí, Ellen; Klotz, Sigrid; Vidal-Robau, Nuria; Ricken, Gerda; Regelsberger, Günther; Ströbel, Thomas; Kalev, Ognian; Leoni, Marlene; Budka, Herbert; Kovács, Gábor G.

doi:10.3390/v13091796

Cited by 3 publications

(2 citation statements)

References 33 publications

(45 reference statements)

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“…Furthermore, a recent study showed that NG2 glia, oligodendrocyte-lineage cells, exert a protective effect against prioninduced neurotoxicity by interacting with microglia and inhibiting critical signalling pathways 79 . It is also noteworthy that in human patients, oligodendroglial PrP pathology has been reported in certain histotypes of sCJD 80 . Therefore, oligodendrocytes may be implicated in prion pathogenesis, which is further supported by the convergence of the two non-PRNP sCJD risk factors, STX6 and GAL3ST1, in this cell type.…”

Section: Discussionmentioning

confidence: 95%

Multiomic Analyses Direct Hypotheses for Creutzfeldt-Jakob Disease Risk Genes

Küçükali,

Hill,

Watzeels

et al. 2024

Preprint

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Prions are assemblies of misfolded prion protein that cause several fatal and transmissible neurodegenerative diseases, with the most common phenotype in humans being sporadic Creutzfeldt-Jakob disease (sCJD). Aside from variation of the prion protein itself, molecular risk factors are not well understood. Prion and prion-like mechanisms are thought to underpin common neurodegenerative disorders meaning that the elucidation of mechanisms could have broad relevance. Herein we sought to further develop our understanding of the factors that confer risk of sCJD using a systematic gene prioritization and functional interpretation pipeline based on multiomic integrative analyses. We integrated the published sCJD genome-wide association study (GWAS) summary statistics with publicly available bulk brain and brain cell type gene and protein expression datasets. We performed multiple transcriptome and proteome-wide association studies (TWAS & PWAS) and Bayesian genetic colocalization analyses between sCJD risk association signals and multiple brain molecular quantitative trait loci signals. We then applied our systematic gene prioritization pipeline on the obtained results and nominated prioritized sCJD risk genes with risk-associated molecular mechanisms in a transcriptome and proteome-wide manner. Genetic upregulation of both gene and protein expression of syntaxin-6 (STX6) in the brain was associated with sCJD risk in multiple datasets, with a risk-associated gene expression regulation specific to oligodendrocytes. Similarly, increased gene and protein expression of protein disulfide isomerase family A member 4 (PDIA4), involved in the unfolded protein response, was linked to increased disease risk, particularly in excitatory neurons. Protein expression of mesencephalic astrocyte derived neurotrophic factor (MANF), involved in protection against endoplasmic reticulum stress and sulfatide binding (linking to the enzyme in the final step of sulfatide synthesis, encoded by sCJD risk geneGAL3ST1), was identified as protective against sCJD. In total 32 genes were prioritized into two tiers based on level of evidence and confidence for further studies. This study provides insights into the genetically-associated molecular mechanisms underlying sCJD susceptibility and prioritizes several specific hypotheses for exploration beyond the prion protein itself and beyond the previously highlighted sCJD risk loci through the newly prioritized sCJD risk genes and mechanisms. These findings highlight the importance of glial cells, sulfatides and the excitatory neuron unfolded protein response in sCJD pathogenesis.

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Section: Discussionmentioning

confidence: 95%

Multiomic Analyses Direct Hypotheses for Creutzfeldt-Jakob Disease Risk Genes

Küçükali,

Hill,

Watzeels

et al. 2024

Preprint

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“…The differing morphologies of plaque‐like deposits depending on the regions might also be a characteristic of MV2K + C. Furthermore, we found synaptic immunoreactive structures along the axons in the cerebral cortex, and this finding probably includes perineuronal apical axon staining. The coarse deposits along the axon have been frequently seen in VV2 but are not often described in MV2K + C 19 . The neuropathological feature of MV2K is similar to VV2 2 .…”

Section: Discussionmentioning

confidence: 99%

An autopsy case of MV 2K + C subtype of Creutzfeldt–Jakob disease

Uchino,

Saito,

Tokuda

et al. 2024

Neuropathology

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Methionine/valine (MV) 2 type of sporadic Creutzfeldt–Jakob (sCJD) is divided into three subtypes based on neuropathological criteria: MV2‐kuru (MV2K), MV2‐cortical (MV2C), and MV2K + C, exhibiting the co‐occurrence of these two pathological features. We report an autopsy case of MV2K + C subtype of sCJD. A 46‐year‐old Japanese man began to make mistakes at work. Two months later, he gradually developed gait instability. The initial neurological examination revealed limb ataxia and myoclonus. Diffusion‐weighted images (DWI) showed a hyperintensity in the right frontal cortex, basal ganglia, and thalamus. Ten months after the onset of disease, he fell into akinetic mutism. He died at 47 years of age, 12 months after the initial presentation. Pathological investigation revealed microvacuolation and confluent vacuoles in the cerebral cortex. In the basal ganglia and thalamus, there was severe neuronal loss and gliosis with mild spongiform change. Kuru plaques were found within the cerebellum. Prion protein (PrP) immunostaining revealed synaptic, perivacuolar, perineuronal, and plaque‐like deposits in the cerebral cortex. There were synaptic and plaque‐like PrP deposits in the basal ganglia, thalamus, and granular cell layer of the cerebellum. In these areas, plaque‐like deposits mainly consisted of small deposits, whereas plaque‐like deposits in the cerebral cortex consisted both of coarse granular and small deposits. Analysis of the PrP gene showed no pathogenic mutations, and Western blot examination revealed a mixture of type 2 and intermediate‐type PrP. The progressive cognitive decline and ataxia in addition to the hyperintensity in the basal ganglia and/or thalamus on DWI are the basis for clinical diagnosis of MV2. The severe gliosis in the basal ganglia and various morphologies of plaque‐like deposits that differ by the region may be characteristic of MV2K + C. Detailed neuropathological examination together with Western blot analysis is important to collect more cases for elucidating the pathogenesis of MV2K + C.

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