プリオン病

Most human-acquired prion diseases result from infection with M1 or V2 prions from sporadic Creutzfeldt-Jakob disease. To prevent transmission via surgical instruments, sterilization methods targeting these prions are essential. In this study, stainless steel wires coated with M1 or V2 prions were used to evaluate inactivation protocols. None of the individual treatments - autoclaving, SDS or NaOH - eliminated infectivity except for autoclaving against V2 prions. Autoclaving at 134 °C revealed distinct thermal stability between M1 and V2, with M1 exhibiting greater thermal stability. Importantly, combining methods, which we herein called two-step processing methods, achieved practical inactivation: SDS treatment followed by autoclaving at 121 °C was highly effective. Commercial alkaline detergents also proved effective against M1 prion under a combination of high pH and temperature. The inability to detect infection in our model mice using our assay system demonstrates that the infectivity titre decreased to 10⁻⁸ in M1 and 10⁻⁷ in V2. These findings indicate that synergistic approaches can achieve prion inactivation under practical conditions, supporting the need for revised sterilization protocols to prevent iatrogenic transmission.

Parkinson's disease (PD) is characterized by the progressive accumulation and prion-like spread of pathological α-synuclein (α-syn). Increasing evidence suggests that α-syn pathology may originate in the gastrointestinal tract before spreading to the central nervous system; however, the intestinal mechanisms that initiate pathological α-syn phosphorylation and intercellular transfer remain poorly understood. Here, we investigated the role of Toll-like receptor 2 (TLR2) in regulating α-syn phosphorylation using intestinal epithelial cell model. We found that pSer129-positive α-syn immunoreactivity and TLR2 expression progressively increased in the mouse jejunum during aging. Although pSer129-positive structures did not substantially colocalize with chromogranin A-positive enteroendocrine cells, we confirmed that TLR2 is expressed in a subset of these cells in vivo. Furthermore, analysis of single-cell transcriptomic data from mouse enteroendocrine cells and human colonic organoids revealed that a small subset of enteroendocrine cells express TLR2. We therefore used the enteroendocrine cell line STC-1 as an in vitro model to investigate TLR2-dependent α-syn phosphorylation in an enteroendocrine-like context. In STC-1 cells, TLR2 enhanced the cellular uptake of extracellular α-syn preformed fibrils (PFFs), promoted the generation of pSer129 α-syn and higher molecular weight α-syn species, and facilitated the extracellular release of factors that increased pSer129 immunoreactivity in recipient cells. Pharmacological inhibition of TLR2 attenuated PFF uptake and pSer129 α-syn generation. Conditioned medium from TLR2-overexpressing STC-1 cells increased pSer129 α-syn immunoreactivity in recipient neuronal cells, suggesting that TLR2 may promote the release of soluble factors capable of inducing α-syn phosphorylation in recipient cells. The molecular identity of the transferred factor(s) and the underlying mechanism remain to be determined. Collectively, our findings identify TLR2 as a regulator of α-syn uptake, phosphorylation, and release in an enteroendocrine cell model. These results support a potential role for aging-associated upregulation of intestinal TLR2 in modulating α-syn phosphorylation, although the in vivo cellular source of pSer129 α-syn and the contribution of enteroendocrine cells require further investigation.

Language often incorporates mechanistic assumptions. Terms used to describe protein behavior and properties, such as "accumulation," "replication," "propagation," and "strains," largely borrowed from prion biology and investigated in animal models, have shaped how Parkinson disease is understood. Similarly, clinical constructs such as "phenoconversion," "prodrome," "resilience," and "copathology" embed assumptions about disease onset and pathogenicity. In this article, we explore how our vocabulary has contributed to the transformation of hypotheses into widely accepted conventions. We argue that greater precision in language may help clarify the difference between observation and inference: Aggregated proteins can be described as pathologic deposits representing the insoluble fraction of proteins no longer in their soluble functional state, their variants as polymorphs rather than "strains," and seeding phenomena as nucleation-dependent aggregation or precipitation rather than replication. Such distinctions avoid conflating pathologic observations with etiology and have implications for biomarker interpretation, taxonomy, and therapeutic innovation.

Creutzfeldt-Jakob disease (CJD) exemplifies a cruel paradox of modern neurology: we can now diagnose it with near-perfect accuracy within hours, yet we cannot alter its invariably fatal course. The advent of cerebrospinal fluid (CSF) and skin real-time quaking-induced conversion (RT-QuIC), coupled with high-specificity brain MRI, has enabled robust ante-mortem diagnostic support for CJD, which was previously only definitively established post-mortem. Yet no disease-modifying therapy exists. Drawing on a molecularly supported case of sporadic CJD, this Perspective argues that the widening gap between diagnostic precision and therapeutic impotence is not merely a failure of prion medicine-it is a stress test for the entire rare-disease ecosystem. We examine how this diagnostic triumph creates an unprecedented opportunity for presymptomatic intervention, ultra-adaptive clinical trials, and synergistic combination therapies, and we propose a strategic roadmap to ensure that the next patient diagnosed within hours has a chance, however slim, of a different outcome.

Alzheimer's disease (AD) affects about fifty million people worldwide. Its main characteristics are the formation of amyloid deposits and of neurofibrillary tangles, and cognition loss. To date, no clear etiology for this disease has been identified. Metal ions have been shown to accumulate in amyloid deposits. Moreover, multiple infections have been shown to be risk factors for the development of AD and other dementia, with vaccines playing protective roles. I will here elaborate on the likelihood that amyloid-β is not dominantly a toxic molecule, but a protective protein fragment. A combination of chemical and biological exposures, with metals and infections playing key roles, would be essential factors in late-onset cases of AD. A new, translational mechanistic proposal is presented here, combining abundant experimental results and ideas from the fields of biochemistry, coordination chemistry and immunology.