An astrocyte cell line that differentially propagates murine prions

Tahir, Waqas; Abdulrahman, Basant; Abdelaziz, Dalia H.; Thapa, Simrika; Walia, Rupali; Schätzl, Hermann

doi:10.1074/jbc.ra120.012596

Cited by 19 publications

(18 citation statements)

References 80 publications

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“…Astrocytes can replicate and accumulate PrP Sc independently of neurons [ 35 – 38 ]. Astrocytes were found to accumulate prions early, ahead of neuropathological changes involving vacuolation or neuronal loss [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

Non-cell autonomous astrocyte-mediated neuronal toxicity in prion diseases

Kushwaha

Sinha

Makarava

et al. 2021

acta neuropathol commun

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Under normal conditions, astrocytes perform a number of important physiological functions centered around neuronal support and synapse maintenance. In neurodegenerative diseases including Alzheimer’s, Parkinson’s and prion diseases, astrocytes acquire reactive phenotypes, which are sustained throughout the disease progression. It is not known whether in the reactive states associated with prion diseases, astrocytes lose their ability to perform physiological functions and whether the reactive states are neurotoxic or, on the contrary, neuroprotective. The current work addresses these questions by testing the effects of reactive astrocytes isolated from prion-infected C57BL/6J mice on primary neuronal cultures. We found that astrocytes isolated at the clinical stage of the disease exhibited reactive, pro-inflammatory phenotype, which also showed downregulation of genes involved in neurogenic and synaptogenic functions. In astrocyte-neuron co-cultures, astrocytes from prion-infected animals impaired neuronal growth, dendritic spine development and synapse maturation. Toward examining the role of factors secreted by reactive astrocytes, astrocyte-conditioned media was found to have detrimental effects on neuronal viability and synaptogenic functions via impairing synapse integrity, and by reducing spine size and density. Reactive microglia isolated from prion-infected animals were found to induce phenotypic changes in primary astrocytes reminiscent to those observed in prion-infected mice. In particular, astrocytes cultured with reactive microglia-conditioned media displayed hypertrophic morphology and a downregulation of genes involved in neurogenic and synaptogenic functions. In summary, the current study provided experimental support toward the non-cell autonomous mechanisms behind neurotoxicity in prion diseases and demonstrated that the astrocyte reactive phenotype associated with prion diseases is synaptotoxic.

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Section: Introductionmentioning

confidence: 99%

Non-cell autonomous astrocyte-mediated neuronal toxicity in prion diseases

Kushwaha

Sinha

Makarava

et al. 2021

acta neuropathol commun

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“…Recently, human-induced pluripotent stem cell (iPSC)-derived astrocytes have been successfully established to efficiently replicate human prions in a cell culture model [ 36 ]. An immortalized mouse astrocyte cell line could selectively and differentially propagate different murine prions [ 37 ]. Taken together, these results suggest that astrocytes play a critical role in prion propagation and pathogenesis.…”

Section: Neuroinflammation In Prion Diseasementioning

confidence: 99%

Neuroinflammation in Prion Disease

Chen

Zhu

2021

IJMS

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Neuroinflammation, typically manifest as microglial activation and astrogliosis accompanied by transcriptomic alterations, represents a common hallmark of various neurodegenerative conditions including prion diseases. Microglia play an overall neuroprotective role in prion disease, whereas reactive astrocytes with aberrant phenotypes propagate prions and contribute to prion-induced neurodegeneration. The existence of heterogeneous subpopulations and dual functions of microglia and astrocytes in prion disease make them potential targets for therapeutic intervention. A variety of neuroinflammation-related molecules are involved in prion pathogenesis. Therapeutics targeting neuroinflammation represents a novel approach to combat prion disease. Deciphering neuroinflammation in prion disease will deepen our understanding of pathogenesis of other neurodegenerative disorders.

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“…Additionally, Western blot showed much lower levels of PK-resistant PrP Sc in cells infected with RML as compared with 22L. However, real-time quaking-induced conversion (RT-QuIC) demonstrated that RML-infected cells had greater seeding activity than 22L-infected cells [ 44 ].…”

Section: Immortalized Cell Linesmentioning

confidence: 99%

From Cell Culture to Organoids-Model Systems for Investigating Prion Strain Characteristics

Pineau

Sim

2021

Biomolecules

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Prion diseases are the hallmark protein folding neurodegenerative disease. Their transmissible nature has allowed for the development of many different cellular models of disease where prion propagation and sometimes pathology can be induced. This review examines the range of simple cell cultures to more complex neurospheres, organoid, and organotypic slice cultures that have been used to study prion disease pathogenesis and to test therapeutics. We highlight the advantages and disadvantages of each system, giving special consideration to the importance of strains when choosing a model and when interpreting results, as not all systems propagate all strains, and in some cases, the technique used, or treatment applied, can alter the very strain properties being studied.

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An astrocyte cell line that differentially propagates murine prions

Cited by 19 publications

References 80 publications

Non-cell autonomous astrocyte-mediated neuronal toxicity in prion diseases

Non-cell autonomous astrocyte-mediated neuronal toxicity in prion diseases

Neuroinflammation in Prion Disease

From Cell Culture to Organoids-Model Systems for Investigating Prion Strain Characteristics

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