Eukaryotic cells are complex structures capable of coordinating numerous biochemical reactions in space and time. Key to such coordination is the subdivision of intracellular space into functional ...compartments. Compartmentalization can be achieved by intracellular membranes, which surround organelles and act as physical barriers. In addition, cells have developed sophisticated mechanisms to partition their inner substance in a tightly regulated manner. Recent studies provide compelling evidence that membraneless compartmentalization can be achieved by liquid demixing, a process culminating in liquid–liquid phase separation and the formation of phase boundaries. We discuss how this emerging concept may help in understanding dynamic reorganization of subcellular space and highlight its potential as a framework to explain pathological protein assembly in cancer and neurodegeneration.
Microglia play vital roles in the health and diseases of the central nervous system. Loss of microglia homeostatic state is a key feature of brain aging and neurodegeneration. However, the mechanisms ...underlying the maintenance of distinct microglia cellular states are largely unclear. Here, we show that NG2 glia, also known as oligodendrocyte precursor cells, are essential for maintaining the homeostatic microglia state. We developed a highly efficient and selective NG2 glia depletion method using small‐molecule inhibitors of platelet‐derived growth factor (PDGF) signaling in cultured brain slices. We found that loss of NG2 glia abolished the homeostatic microglia signature without affecting the disease‐associated microglia profiles. Similar findings were also observed in vivo by genetically depleting NG2 glia or conditionally inhibiting NG2 glia PDGF signaling in the adult mouse brain. These data suggest that NG2 glia exert a crucial influence onto microglia cellular states that are relevant to brain aging and neurodegenerative diseases. In addition, our results provide a powerful, convenient, and selective tool for the investigation of NG2 glia function.
Main points
Postnatal NG2 glia maintenance obligatorily depends on continuous PDGF signaling.
A highly efficient, selective and versatile NG2 glia depletion method is established.
Loss of NG2 glia abolishes the homeostatic microglia signature both ex vivo and in vivo.
Recent reports indicate that a growing number of intracellular proteins are not only prone to pathological aggregation but can also be released and “infect” neighboring cells. Therefore, many complex ...diseases may obey a simple model of propagation where the penetration of seeds into hosts determines spatial spread and disease progression. We term these proteins prionoids, as they appear to infect their neighbors just like prions—but how can bulky protein aggregates be released from cells and how do they access other cells? The widespread existence of such prionoids raises unexpected issues that question our understanding of basic cell biology.
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland
Transmissible spongiform encephalopathies (TSEs) are inevitably lethal neurodegenerative diseases that affect humans ...and a large variety of animals. The infectious agent responsible for TSEs is the prion, an abnormally folded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein (PrP C ) of the host. PrP C is necessary for prion replication and for prion-induced neurodegeneration, yet the proximal causes of neuronal injury and death are still poorly understood. Prion toxicity may arise from the interference with the normal function of PrP C , and therefore, understanding the physiological role of PrP C may help to clarify the mechanism underlying prion diseases. Here we discuss the evolution of the prion concept and how prion-like mechanisms may apply to other protein aggregation diseases. We describe the clinical and the pathological features of the prion diseases in human and animals, the events occurring during neuroinvasion, and the possible scenarios underlying brain damage. Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics.
The role of innate and adaptive immunity in neurodegeneration remains controversial
Alzheimer's disease (AD), Parkinson's disease (PD), and prion diseases such as Creutzfeldt-Jakob disease attack ...different parts of the central nervous system (CNS) and elicit distinct symptoms, yet they share many biochemical and neuropathological features. These include the formation of protein aggregates in the affected brain regions and progressive activation of non-neuronal cells in the brain that play crucial roles in immune responses. The activation of immune cells in the CNS (“neuroinflammation”) is prominent in these diseases. However, it remains unclear whether boosting or suppressing the immune system, in the brain or in the periphery, may attenuate neurodegeneration. In the case of extraneural prion infections, genetic or pharmacological ablation of components of the immune system, such as B cells and complement, can prevent disease (
1
). However, immunotherapies, which have been successful in treating certain types of cancer, have yet to reverse neurodegeneration in any patients. Therefore, the therapeutic promise of this approach remains debatable.
A growing number of diseases seem to be associated with inappropriate deposition of protein aggregates. Some of these diseases--such as Alzheimer's disease and systemic amyloidoses--have been ...recognized for a long time. However, it is now clear that ordered aggregation of pathogenic proteins does not only occur in the extracellular space, but in the cytoplasm and nucleus as well, indicating that many other diseases may also qualify as amyloidoses. The common structural and pathogenic features of these diverse protein aggregation diseases is only now being fully understood, and may provide novel opportunities for overarching therapeutic approaches such as depleting the monomeric precursor protein, inhibiting aggregation, enhancing aggregate clearance or blocking common aggregation-induced cellular toxicity pathways.
A role for astroglia in prion diseases Aguzzi, Adriano; Liu, Yingjun
The Journal of experimental medicine,
12/2017, Volume:
214, Issue:
12
Journal Article
Peer reviewed
Open access
In this issue of JEM, Krejciova et al. (https://doi.org/10.1084/jem.20161547) report that astrocytes derived from human iPSCs can replicate human CJD prions. These observations provide a new, ...potentially very valuable model for studying human prions in cellula and for identifying antiprion compounds that might serve as clinical candidates. Furthermore, they add to the evidence that astrocytes may not be just innocent bystanders in prion diseases.
Microglia are resident immune cells in the brain and spinal cord. These cells provide immune surveillance and are mobilized in response to disparate diseases and injuries. Although microglial ...activation is often considered neurotoxic, microglia are essential defenders against many neurodegenerative diseases. It also seems increasingly likely that microglial dysfunction can underlie certain neurological diseases without an obvious immune component.
The misfolding of the cellular prion protein (PrP
) causes fatal neurodegenerative diseases. Yet PrP
is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its ...evolutionary elimination. Ablation of PrP
in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrP
, but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrP
in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.
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