How is alpha‐synuclein cleared from the cell?

Stefanis, Leonidas; Emmanouilidou, Evangelia; Pantazopoulou, Marina; Kirik, Deniz; Vekrellis, Kostas; Tofaris, George K.

doi:10.1111/jnc.14704

Cited by 128 publications

(127 citation statements)

References 131 publications

(304 reference statements)

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“…Overexpression of human α-syn in the substantia nigra of immune competent mice results in microglial activation, MHC II activation, T cell and monocyte entry into the brain and consequently, loss of substantia nigra neurons [33,60,61]. Our findings support these prior studies by showing that intrastriatal injection of human α-syn PFFs leads to elevated phosphorylated α-syn pathology in immunodeficient compared to wildtype mice [62]. The exacerbation of pathology observed in PFFs injected immunocompromised mice was partially mitigated by adoptive transfer of T cells.…”

Section: Discussionsupporting

confidence: 88%

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

George¹,

Tyson²,

Rey

et al. 2020

Preprint

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α-Synuclein (α-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of αsynucleinopathies, such as Parkinson's disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells.These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from α-syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key to the pathogenesis of the disease.To study the role of the adaptive immune system with respect to α-syn pathology, we injected human α-syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated α-syn pathology as well as microgliosis. Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated α-syn pathology in the substantia nigra. We also reconstituted T and B cell populations in the NSG mice with cells isolated from a wildtype mouse spleen. Interestingly, reconstituting the T cell population decreased the accumulation of α-syn pathology and resulted in persistent microgliosis when compared to non-transplanted mice; reconstitution of B cells did not alter the nigral neuropathology. Our work provides experimental evidence that T cells play a role in the pathogenesis of α-synucleinopathies.

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Section: Discussionsupporting

confidence: 88%

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

George¹,

Tyson²,

Rey

et al. 2020

Preprint

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“…Recently, it has been proposed that astrocyte and microglia could participate in the exosome-mediated clearance of α-synuclein [70]. However, the absence of α-synuclein immunoreactivity in GFAP (+) cells does not support such a role for astrocytes.…”

Section: Discussionmentioning

confidence: 97%

Unilateral intranigral administration of β-sitosterol β-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat

Soto-Rojas

Martínez-Dávila

Luna-Herrera

et al. 2020

acta neuropathol commun

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The spreading and accumulation of α-synuclein and dopaminergic neurodegeneration, two hallmarks of Parkinson's disease (PD), have been faithfully reproduced in rodent brains by chronic, oral administration of β-sitosterol β-Dglucoside (BSSG). We investigated whether a single injection of BSSG (6 μg BSSG/μL DMSO) in the left substantia nigra of Wistar rats causes the same effects. Mock DMSO injections and untreated rats formed control groups. We performed immunostainings against the pathological α-synuclein, the dopaminergic marker tyrosine hydroxylase (TH), the neuroskeleton marker β-III tubulin, the neurotensin receptor type 1 (NTSR1) as non-dopaminergic phenotype marker and Fluro-Jade C (F-J C) label for neurodegeneration. Using β-galactosidase (β-Gal) assay and active caspase-3 immunostaining, we assessed cell death mechanisms. Golgi-Cox staining was used to measure the density and types of dendritic spines of striatal medium spiny neurons. Motor and non-motor alterations were also evaluated. The study period comprised 15 to 120 days after the lesion. In the injured substantia nigra, BSSG caused a progressive α-synuclein aggregation and dopaminergic neurodegeneration caused by senescence and apoptosis. The α-synuclein immunoreactivity was also present within microglia cells. Decreased density of dopaminergic fibers

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“…While experimental evidence on the role of UPS in metabolizing α-syn dates back to the early 2000s [52,[117][118][119]140,[144][145][146][147] the implication of autophagy was evident a few years later, and fully confirmed in recent in vivo studies on ATG7-depleted DA neurons [121][122][123]. These studies indicate that both UPS and autophagy are seminal for the survival of DA neurons, since inhibition of either pathway leads to parkinsonism featuring a massive loss of midbrain DA neurons and α-syn accumulation within ubiquitin-positive Lewy body-like inclusions in surviving neurons [119,121,122,140].…”

Section: Alpha-synucleinmentioning

confidence: 99%

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Limanaqi

Biagioni

Gambardella

et al. 2020

IJMS

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Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies.

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How is alpha‐synuclein cleared from the cell?

Cited by 128 publications

References 131 publications

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

Unilateral intranigral administration of β-sitosterol β-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

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