Search

The transmission of prions across species is a critical aspect of their dissemination among mammalian hosts, including humans. This process often necessitates strain adaptation. In this study, we sought to investigate the mechanisms underlying prion adaptation while mitigating biases associated with the history of cross-species transmission of natural prion strains. To achieve this, we utilized the synthetic hamster prion strain S05. Propagation of S05 using mouse PrPC in Protein Misfolding Cyclic Amplification did not immediately overcome the species barrier. This finding underscores the involvement of factors beyond disparities in primary protein structures. Subsequently, we performed five serial passages to stabilize the incubation time to disease in mice. The levels of PrPSc increased with each passage, reaching a maximum at the third passage, and declining thereafter. This suggests that only the initial stage of adaptation is primarily driven by an acceleration in PrPSc replication. During the protracted adaptation to a new host, we observed significant alterations in the glycoform ratio and sialylation status of PrPSc N-glycans. These changes support the notion that qualitative modifications in PrPSc contribute to a more rapid disease progression. Furthermore, consistent with the decline in sialylation, a cue for “eat me” signaling, the newly adapted strain exhibited preferential colocalization with microglia. In contrast to PrPSc dynamics, the intensity of microglia activation continued to increase after the third passage in the new host. In summary, our study elucidates that the adaptation of a prion strain to a new host is a multi-step process driven by several factors.

Prion diseases are a group of fatal neurodegenerative diseases caused by misfolding of the normal cellular form of the prion protein or PrPC, into a disease-associated self-replicating state or PrPSc. PrPC and PrPSc are posttranslationally modified with N-linked glycans, in which the terminal positions occupied by sialic acids residues are attached to galactose predominantly via α2-6 linkages. The sialylation status of PrPSc is an important determinant of prion disease pathogenesis, as it dictates the rate of prion replication and controls the fate of prions in an organism. The current study tests whether a knockout of ST6Gal1, one of the two mammalian sialyltransferases that catalyze the sialylation of glycans via α2-6 linkages, reduces the sialylation status of PrPSc and alters prion disease pathogenesis. We found that a global knockout of ST6Gal1 in mice significantly reduces the α2-6 sialylation of the brain parenchyma, as determined by staining with Sambucus Nigra agglutinin. However, the sialylation of PrPSc remained stable and the incubation time to disease increased only modestly in ST6Gal1 knockout mice (ST6Gal1-KO). A lack of significant changes in the PrPSc sialylation status and prion pathogenesis is attributed to the redundancy in sialylation and, in particular, the plausible involvement of a second member of the sialyltransferase family that sialylate via α2-6 linkages, ST6Gal2.

Chronic neuroinflammation involves reactive microgliosis and astrogliosis, and is regarded as a common pathological hallmark of neurodegenerative diseases including Alzheimer’s, Parkinson’s, ALS and prion diseases. Reactive astrogliosis, routinely observed immunohistochemically as an increase in glial fibrillary acidic protein (GFAP) signal, is a well-documented feature of chronic neuroinflammation associated with neurodegenerative diseases. Recent studies on single-cell transcriptional profiling of a mouse brain revealed that, under normal conditions, several distinct subtypes of astrocytes with regionally specialized distribution exist. However, it remains unclear whether astrocytic response to pro-inflammatory pathological conditions is uniform across whole brain or is region-specific. The current study compares the response of microglia and astrocytes to prions in mice infected with 22L mouse-adapted prion strain. While the intensity of reactive microgliosis correlated well with the extent of PrPSc deposition, reactive astrogliosis displayed a different, region-specific pattern. In particular, the thalamus and stratum oriens of hippocampus, which are both affected by 22L prions, displayed strikingly different response of astrocytes to PrPSc. Astrocytes in stratum oriens of hippocampus responded to accumulation of PrPSc with visible hypertrophy and increased GFAP, while in the thalamus, despite stronger PrPSc signal, the increase of GFAP was milder than in hippocampus, and the change in astrocyte morphology was less pronounced. The current study suggests that astrocyte response to prion infection is heterogeneous and, in part, defined by brain region. Moreover, the current work emphasizes the needs for elucidating region-specific changes in functional states of astrocytes and exploring the impact of these changes to chronic neurodegeneration.