Highly infectious prions are not directly neurotoxic

Benilova, Iryna; Reilly, M.; Terry, Cassandra; Wenborn, Adam; Schmidt, Christian; Marinho, Aline T.; Risse, Emmanuel; Al-Doujaily, Huda; Oliveira, Michael Wiggins De; Sandberg, Malin; Wadsworth, Jonathan D. F.; Jat, Parmjit; Collinge, John

doi:10.1073/pnas.2007406117

Cited by 32 publications

(27 citation statements)

References 27 publications

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“…Selective, astrocyte-restrictive targeting of unfolded protein response, which is exuberated in reactive astrocytes, via inhibition of PERK signaling was found to prolong the incubation time to the terminal disease in mice [ 14 ]. Moreover, highly infectious prions lacked direct neurotoxicity, indirectly supporting the hypothesis on a non-cell autonomous mechanism of neurodegeneration [ 17 ]. Together with previous work, the current study argues in support of the non-cell autonomous, astrocyte-driven mechanism behind neurodegeneration.…”

Section: Discussionmentioning

confidence: 72%

“…Moreover, partial depletion of microglia exacerbated the reactive phenotype of astrocytes and accelerated disease progression [ 16 ]. Highly infectious prions purified from animals were not directly neurotoxic, supporting the hypothesis on a non-autonomous mechanism being behind prion neurotoxicity [ 17 ]. Indeed, reactive astrocytes isolated from prion-infected animals exhibited synaptotoxic phenotypes characterized by impairment of neuronal growth, inhibition of dendritic spine development and synapse maturation along with impairment of synapse integrity [ 15 ].…”

Section: Introductionmentioning

confidence: 62%

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The degree of astrocyte activation is predictive of the incubation time to prion disease

Makarava

Mychko

Chang

et al. 2021

acta neuropathol commun

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In neurodegenerative diseases including Alzheimer’s, Parkinson’s and prion diseases, astrocytes acquire disease-associated reactive phenotypes. With growing appreciation of their role in chronic neurodegeneration, the questions whether astrocytes lose their ability to perform homeostatic functions in the reactive states and whether the reactive phenotypes are neurotoxic or neuroprotective remain unsettled. The current work examined region-specific changes in expression of genes, which report on astrocyte physiological functions and their reactive states, in C57Black/6J mice challenged with four prion strains via two inoculation routes. Unexpectedly, strong reverse correlation between the incubation time to the diseases and the degree of astrocyte activation along with disturbance in functional pathways was observed. The animal groups with the most severe astrocyte response and degree of activation showed the most rapid disease progression. The degree of activation tightly intertwined with the global transformation of the homeostatic state, characterized by disturbances in multiple gene sets responsible for normal physiological functions producing a neurotoxic, reactive phenotype as a net result. The neurotoxic reactive phenotype exhibited a universal gene signature regardless of the prion strain. The current work suggests that the degree of astrocyte activation along with the disturbance in their physiological pathways contribute to the faster progression of disease and perhaps even drive prion pathogenesis.

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Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 62%

The degree of astrocyte activation is predictive of the incubation time to prion disease

Makarava

Mychko

Chang

et al. 2021

acta neuropathol commun

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“…Furthermore, uniform mechanism of PrP Sc toxicity does not elaborate on the question of why brain regions exhibit strikingly different, strain-specific vulnerability to PrP Sc [ 82 , 83 ]. Recent studies demonstrated that highly infectious prions are not directly neurotoxic [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, it is not known whether upon activation, astrocytes acquire neuroprotective or neurotoxic phenotypes. Recent studies illustrated that highly infectious prions are not directly neurotoxic [ 51 ], raising a possibility that mechanisms alternative to the direct toxicity of PrP Sc to neurons exists.…”

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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“…However, there is still controversy about the neurotoxicity of PrP Sc . Benilova et al demonstrated that purified highly infectious prions are not neurotoxic, although the whole brain extracts of prion-infected mice were neurotoxic [ 89 ]. Considering that soluble oligomers of AβP are neurotoxic and AβP fibrils are nontoxic [ 90 ], the involvements of the conformation of PrP and its neurotoxicity might be complex.…”

Section: Toxic Functions Of Prp and Neurometalsmentioning

confidence: 99%

Neurometals in the Pathogenesis of Prion Diseases

Kawahara

Kato-Negishi

Tanaka

2021

IJMS

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Prion diseases are progressive and transmissive neurodegenerative diseases. The conformational conversion of normal cellular prion protein (PrPC) into abnormal pathogenic prion protein (PrPSc) is critical for its infection and pathogenesis. PrPC possesses the ability to bind to various neurometals, including copper, zinc, iron, and manganese. Moreover, increasing evidence suggests that PrPC plays essential roles in the maintenance of homeostasis of these neurometals in the synapse. In addition, trace metals are critical determinants of the conformational change and toxicity of PrPC. Here, we review our studies and other new findings that inform the current understanding of the links between trace elements and physiological functions of PrPC and the neurotoxicity of PrPSc.

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Highly infectious prions are not directly neurotoxic

Cited by 32 publications

References 27 publications

The degree of astrocyte activation is predictive of the incubation time to prion disease

The degree of astrocyte activation is predictive of the incubation time to prion disease

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

Neurometals in the Pathogenesis of Prion Diseases

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