Rapid ex vivo reverse genetics identifies the essential determinants of prion protein toxicity

The cellular prion protein PrP$^{C}$ mediates the neurotoxicity of prions and other protein aggregates through poorly understood mechanisms. Antibody-derived ligands against the globular domain of PrP$^{C}$ (GDL) can also initiate neurotoxicity by inducing an intramolecular R$_{208}$ -H$_{140}$ hydrogen bond ("H-latch") between the α2-α3 and β2-α2 loops of PrP$^{C}$ . Importantly, GDL that suppresses the H-latch prolong the life of prion-infected mice, suggesting that GDL toxicity and prion infections exploit convergent pathways. To define the structural underpinnings of these phenomena, we transduced 19 individual PrP$^{C}$ variants to PrP$^{C}$ -deficient cerebellar organotypic cultured slices using adenovirus-associated viral vectors (AAV). We report that GDL toxicity requires a single N-proximal cationic residue (K$_{27}$ or R$_{27}$ ) within PrP$^{C}$ . Alanine substitution of K$_{27}$ also prevented the toxicity of PrP$^{C}$ mutants that induce Shmerling syndrome, a neurodegenerative disease that is suppressed by co-expression of wild-type PrP$^{C}$ . K$_{27}$ may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration

Bridging the age gap: a review of molecularly informed treatments for glioma in adolescents and young adults

Gliomas are the most common primary central nervous system (CNS) tumors and a major cause of cancer-related mortality in children (age 39 years). Molecular pathology has helped enhance the characterization of these tumors, revealing a heterogeneous and ever more complex group of malignancies. Recent molecular analyses have led to an increased appreciation of common genomic alterations prevalent across all ages. The 2021 World Health Organization (WHO) CNS tumor classification, 5th edition (WHO CNS5) brings forward a nomenclature distinguishing "pediatric-type" and "adult-type" gliomas. The spectrum of gliomas in AYA comprises both "pediatric-like" and "adult-like" tumor entities but remains ill-defined. With fragmentation of clinical management between pediatric and adult centers, AYAs face challenges related to gaps in medical care, lower rates of enrollment in clinical trials and additional psychosocial and economic challenges. This calls for a rethinking of diagnostic and therapeutic approaches, to improve access to appropriate testing and potentially beneficial treatments to patients of all ages

A conformational switch controlling the toxicity of the prion protein

Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (‘H-latch’), altering the flexibility of the α2–α3 and β2–α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity

LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies.

While the initial pathology of Parkinson's disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid

A first update on mapping the human genetic architecture of COVID-19

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Correction: Prion infections and anti-PrP antibodies trigger converging neurotoxic pathways.

[This corrects the article DOI: 10.1371/journal.ppat.1004662.]

Differential toxicity of antibodies to the prion protein

Antibodies against the prion protein PrPC can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. However, the safety profile of such antibodies is controversial. It was originally reported that the monoclonal antibody D13 exhibits strong target-related toxicity, yet a subsequent study contradicted these findings. We have reported that several antibodies against certain epitopes of PrPC, including antibody POM1, are profoundly neurotoxic, yet antibody ICSM18, with an epitope that overlaps with POM1, was reported to be innocuous when injected into mouse brains. In order to clarify this confusing situation, we assessed the neurotoxicity of antibodies D13 and ICSM18 with dose-escalation studies using diffusion-weighted magnetic resonance imaging and various histological techniques. We report that both D13 and ICSM18 induce rapid, dose-dependent, on-target neurotoxicity. We conclude that antibodies directed to this region may not be suitable as therapeutics. No such toxicity was found when antibodies against the flexible tail of PrPC were administered. Any attempt at immunotherapy or immunoprophylaxis of prion diseases should account for these potential untoward effects

Inflammatory olfactory neuropathy in two patients with COVID-19

We report two cases of olfactory neuropathy diagnosed at autopsy in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. One patient experienced anosmia. Information about anosmia was not available in the other patient. Patient 1, a man aged 70 years, and patient 2, a man aged 79 years, both tested positive for SARS-CoV-2. Patient 1 was a renal transplant recipient with coronary artery disease and arterial hypertension. He developed progressive respiratory failure due to COVID-19 pneumonia and required mechanical ventilation. He was treated with hydroxychloroquine (total 1600 mg). Patient 2 was previously diagnosed with severe pulmonary hypertension and was admitted with fever, cough, and increasing dyspnoea as well as loss of taste and smell. He was also treated with hydroxychloroquine (total 1600 mg); however, he declined invasive treatment. Patient 1 died 8 days after hospital admission; patient 2 died 6 days after hospital admission