α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading

Loría, Frida; Vargas, Jessica; Bousset, Luc; Syan, Sylvie; Salles, Audrey; Melki, Ronald; Zurzolo, Chiara

doi:10.1007/s00401-017-1746-2

Cited by 209 publications

(188 citation statements)

References 58 publications

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“…Theoretically there are a number of processes that one could target in an attempt to directly reduce α‐synuclein toxicity ranging from protein synthesis, misfolding, fibril formation and aggregation, degradation, and cell‐to‐cell transmission. Most of these processes involve the affected neurons, however, recent work suggests that another alternative could be the enhancement of astrocytic trapping and degradation of α‐synuclein fibrils . Many of the proposed therapeutic approaches remain at the theoretical or planning stages .…”

Section: Targets For Disease Modificationmentioning

confidence: 99%

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

2018

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The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows the relentless progression of the neurodegenerative process. The concept of "disease modification" encompasses intervention types ranging from those designed to slow the underlying degeneration to treatments directed at regenerating or replacing lost neurons. To date all attempts to develop effective disease-modifying therapy have failed. Many reasons have been proposed for these failures including our rudimentary understanding of disease pathogenesis and the assumption that each targeted mechanisms of disease apply to most patients with the same clinical diagnosis. Here we review all aspects of this broad field including general concepts and past challenges followed by a discussion of treatment approaches under the following 4 categories: (1) α-synuclein, (2) pathogenic mechanisms distinct from α-synuclein (most also potentially triggered by α-synuclein toxicity), (3) non-SNCA genetic subtypes of "PD," and (4) possible disease-modifying interventions not directly influencing the underlying PD pathobiology. We emphasize treatments that are currently under active clinical development and highlight a wide range of important outstanding questions and concerns that will need to be considered to advance the field of disease modification in PD. Critically, it is unknown whether the dysfunctional molecular pathways/organelles amenable to modification occur in a sequential fashion across most clinically affected individuals or manifest differentially in independent molecular subtypes of PD. It is possible that there is no "order of disruption" applicable to most patients but, rather, "type of disruption" applicable to subtypes dependent on unknown factors, including genetic variability and other causes for heterogeneity in PD. Knowing when (early vs late), which (eg, synaptic transmission, endosomal sorting and maturation, lysosomal degradation, mitochondrial biogenesis), and in whom (PD subtype) specific disrupted cell pathways are truly pathogenic versus compensatory or even protective, will be important in considering the use of single or combined ("cocktails") putative disease-modifying therapies to selectively target these processes. Beyond the current phase 2 or 3 studies underway evaluating treatments directed at oxidative stress (inosine), cytosolic Ca (isradipine), iron (deferiprone), and extracellular α-synuclein (passive immunization), and upcoming trials of interventions affecting c-Abl, glucagon-like peptide-1, and glucocerebrosidase, it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past. © 2018 International Parkinson and Movement Disorder Society.

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Section: Targets For Disease Modificationmentioning

confidence: 99%

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

2018

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“…An age-related elevated inflammatory status might be very important in the context of intercellular protein transfer, since microglia, oligodendrocytes and astroglia (which are all impacted by inflammatory stimuli) are suggested to modulate cell-to-cell transfer of α-syn (reviewed in (Lee et al 2014)). In this regard, oligodendrocytes, astrocytes, and microglia can take up α-syn from the extracellular space in rodent and organotypic slice models (Reyes et al 2014; Thakur et al 2017; Loria et al 2017). In addition, astrocytes appear to sequester and degrade α-syn assemblies (Loria et al 2017).…”

Section: Do Non-neuronal Cells Play a Role In Neuron To Neuron Transmmentioning

confidence: 99%

“…In this regard, oligodendrocytes, astrocytes, and microglia can take up α-syn from the extracellular space in rodent and organotypic slice models (Reyes et al 2014; Thakur et al 2017; Loria et al 2017). In addition, astrocytes appear to sequester and degrade α-syn assemblies (Loria et al 2017). It is conceivable that inflammation-induced changes in glia impair both their efficacy to take up extracellular α-syn and their ability to degrade it.…”

Section: Do Non-neuronal Cells Play a Role In Neuron To Neuron Transmmentioning

confidence: 99%

The concept of alpha-synuclein as a prion-like protein: ten years after

2018

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Parkinson's disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson's disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson's disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha-synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha-synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion-like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson's disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson's disease.

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“…Astrocytes can internalize neuron‐released α‐Syn or PFF α‐Syn species for lysosomal degradation and have been shown to transfer α‐Syn aggregates throughout their own cellular network . This mechanism is probably important for the physiological elimination of misfolded species, given that astrocytes reportedly degrade α‐Syn aggregates more proficiently than neurons . However, because each astrocyte supports contacts with many neurons and synapses, astrocytic dysproteostasis could engender an alternative pathway for purely interneuronal aggregate transmission .…”

Section: Bringing Glia Into Focus In Pd Researchmentioning

confidence: 99%

The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration

Hinkle

Dawson

2019

Movement Disorders

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We recently demonstrated that NLY01, a novel glucagon‐like peptide‐1 receptor agonist, exerts neuroprotective effects in two mouse models of PD in a glia‐dependent manner. NLY01 prevented microglia from releasing inflammatory mediators known to convert astrocytes into a neurotoxic A1 reactive subtype. Importantly, we provided evidence that this neuroprotection was not mediated by a direct action of NLY01 on neurons or astrocytes (e.g., by activating neurotrophic pathways or modulating astrocyte reactivity per se). In the present article, we provide a generalist review of microglia and astrocytes in neurodegeneration and discuss the emerging paradigm of A1 astrocyte neurotoxicity in more detail. We comment on specific inferences that are naturally suggested by our work in this area and the differential level of support it offers to each. Finally, we discuss implications for the overall goal of creating disease‐modifying therapies for PD, survey emerging methodologies for accelerating translational research on glia in neurodegeneration, and describe expected challenges for developing glia‐directed therapies that do not impede essential physiological functions carried out by glia in the CNS. © 2019 International Parkinson and Movement Disorder Society

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α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading

Cited by 209 publications

References 58 publications

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

The concept of alpha-synuclein as a prion-like protein: ten years after

The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration

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