Prion-like Propagation of α-Synuclein Is Regulated by the FcγRIIB-SHP-1/2 Signaling Pathway in Neurons

Choi, Yu Ree; Cha, Seon-Heui; Kang, Seo-Jun; Kim, Jae-Bong; Jou, Ilo; Park, Sang Myun

doi:10.1016/j.celrep.2017.12.009

Cited by 59 publications

(91 citation statements)

References 49 publications

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“…For example, interaction of aggregated a‐syn with FcγRIIB (an inhibitory FcγR) in neurons via endocytosis leads to the phosphorylation of the FcγRIIB immunoreceptor tyrosine‐based inhibitory motif. This phosphorylation through a downstream mechanism involving SH‐containing tyrosine phosphatase 1/2, (SHP 1/2), resulted in enhancement of a‐syn uptake (Choi et al., ). One study reported that the immune receptor lymphocyte activation gene 3 (LAG3) (Mao et al., ) is necessary to mediate the uptake of a‐syn in neurons, although expression of LAG3 in neurons has not been confirmed by other studies and LAG3 may be more relevant for the uptake of a‐syn by immune cells.…”

Section: The Role Of A‐synuclein In the Microglia Response In Parkinsmentioning

confidence: 99%

Immune system responses in Parkinson's disease: Early and dynamic

Tansey

Romero‐Ramos

2018

Eur J of Neuroscience

125

127

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The neuropathological hallmarks of Parkinson's disease (PD) are the degeneration and death of dopamine‐producing neurons in the ventral midbrain, the widespread intraneuronal aggregation of alpha‐synuclein (α) in Lewy bodies and neurites, neuroinflammation, and gliosis. Signs of microglia activation in the PD brain postmortem as well as during disease development revealed by neuroimaging, implicate immune responses in the pathophysiology of the disease. Intensive research during the last two decades has advanced our understanding of the role of these responses in the disease process, yet many questions remain unanswered. A transformative finding in the field has been the confirmation that in vivo microglia are able to respond directly to pathological a‐syn aggregates but also to neuronal dysfunction due to intraneuronal a‐syn toxicity well in advance of neuronal death. In addition, clinical research and disease models have revealed the involvement of both the innate and adaptive immune systems. Indeed, the data suggest that PD leads not only to a microglia response, but also to a cellular and humoral peripheral immune response. Together, these findings compel us to consider a more holistic view of the immunological processes associated with the disease. Central and peripheral immune responses aimed at maintaining neuronal health will ultimately have consequences on neuronal survival. We will review here the most significant findings that have contributed to the current understanding of the immune response in PD, which is proposed to occur early, involve peripheral and brain immune cells, evolve as neuronal dysfunction progresses, and is likely to influence disease progression.

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Section: The Role Of A‐synuclein In the Microglia Response In Parkinsmentioning

confidence: 99%

Immune system responses in Parkinson's disease: Early and dynamic

Tansey

Romero‐Ramos

2018

Eur J of Neuroscience

125

127

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“…There is a bulk of information regarding prion-like propagation of neuronal α-synuclein in several in vivo and vitro paradigms of LBDs (Ulusoy et al, 2015;Rey et al, 2016;Shimozawa et al, 2017;Choi et al, 2018; just to include additional references to those signaled in previous paragraphs).…”

Section: Lewy Body Diseasesmentioning

confidence: 99%

Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner

Ferrer

2018

Progress in Neurobiology

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Oligodendrocytes are in contact with neurons, wrap axons with a myelin sheath that protects their structural integrity, and facilitate nerve conduction. Oligodendrocytes also form a syncytium with astrocytes which interacts with neurons, promoting reciprocal survival mediated by activity and by molecules involved in energy metabolism and trophism. Therefore, oligodendrocytes are key elements in the normal functioning of the central nervous system. Oligodendrocytes are affected following different insults to the central nervous system including ischemia, traumatism, and inflammation. The term oligodendrogliopathy highlights the prominent role of altered oligodendrocytes in the pathogenesis of certain neurological diseases, not only in demyelinating diseases and most leukodystrophies, but also in aging and age-related neurodegenerative diseases with abnormal protein aggregates. Most of these diseases are characterized by the presence of abnormal protein deposits, forming characteristic and specific inclusions in neurons and astrocytes but also in oligodendrocytes, thus signaling their involvement in the disease. Emerging evidence suggests that such deposits in oligodendrocytes are not mere bystanders but rather are associated with functional alterations. Moreover, operative modifications in oligodendrocytes are also detected in the absence of oligodendroglial inclusions in certain diseases. The present review focuses first on general aspects of oligodendrocytes and precursors, and their development and functions, and then introduces and updates alterations and dysfunction of oligodendrocytes in selected neurodegenerative diseases with abnormal protein aggregates such as multiple system atrophy, Lewy body diseases, tauopathies, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration with TDP-43 inclusions (TDP-43 proteinopathies), and Creutzfeldt-Jakob´s disease as a prototypical human prionopathy.

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“…The spread of α‐synuclein aggregation during the course of the disease is suggestive of prion‐like transmission of pathogenic α‐synuclein species, for which there is now extensive evidence . Several animal models based on the concept of injecting preformed α‐synuclein fibril fragments (PFFs) into the brain or peripherally have reinforced the concept of prion‐like transmission and revealed potential receptors such as lymphocyte‐activation gene 3 and FcγRIIB . Exogenous application of PFFs in mice caused aggregation of endogenous α‐synuclein followed by dopamine neuron demise .…”

Section: α‐Synuclein a Key Contributor To Pd Pathologymentioning

confidence: 99%

“…111 Several animal models based on the concept of injecting preformed α-synuclein fibril fragments (PFFs) into the brain or peripherally have reinforced the concept of prion-like transmission [112][113][114][115][116][117] and revealed potential receptors such as lymphocyteactivation gene 3 118 and FcγRIIB. 119 Exogenous application of PFFs in mice caused aggregation of endogenous α-synuclein followed by dopamine neuron demise. 112 Moreover, time-resolved imaging of α-synuclein inclusion-bearing neurons and neighboring neurons without inclusions indicated a selective degeneration of inclusion-bearing cells, providing evidence that α-synuclein aggregation causes neurodegeneration.…”

Section: α-Synuclein Aggregation In Diseasementioning

confidence: 99%

The usual suspects, dopamine and alpha‐synuclein, conspire to cause neurodegeneration

2019

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Parkinson's disease (PD) is primarily a movement disorder driven by the loss of dopamine‐producing neurons in the substantia nigra (SN). Early identification of the oxidative properties of dopamine implicated it as a potential source of oxidative stress in PD, yet few studies have investigated dopamine neurotoxicity in vivo. The discovery of PD‐causing mutations in α‐synuclein and the presence of aggregated α‐synuclein in the hallmark Lewy body pathology of PD revealed another important player. Despite extensive efforts, the precise role of α‐synuclein aggregation in neurodegeneration remains unclear. We recently manipulated both dopamine levels and α‐synuclein expression in aged mice and found that only the combination of these 2 factors caused progressive neurodegeneration of the SN and an associated motor deficit. Dopamine modified α‐synuclein aggregation in the SN, resulting in greater abundance of α‐synuclein oligomers and unique dopamine‐induced oligomeric conformations. Furthermore, disruption of the dopamine‐α‐synuclein interaction rescued dopaminergic neurons from degeneration in transgenic Caenorhabditis elegans models. In this Perspective, we discuss these findings in the context of known α‐synuclein and dopamine biology, review the evidence for α‐synuclein oligomer toxicity and potential mechanisms, and discuss therapeutic implications. © 2019 International Parkinson and Movement Disorder Society

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Prion-like Propagation of α-Synuclein Is Regulated by the FcγRIIB-SHP-1/2 Signaling Pathway in Neurons

Cited by 59 publications

References 49 publications

Immune system responses in Parkinson's disease: Early and dynamic

Immune system responses in Parkinson's disease: Early and dynamic

Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner

The usual suspects, dopamine and alpha‐synuclein, conspire to cause neurodegeneration

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