Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia

Fellner, Lisa; Irschick, Regina; Schanda, Kathrin; Reindl, Markus; Klimaschewski, Lars; Poewe, Werner; Wenning, Gregor K.; Stefanova, Nadia

doi:10.1002/glia.22437

Cited by 579 publications

(599 citation statements)

References 62 publications

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“…IM injection of human Δ71-82 αS was used to test the hypothesis that induction of αS pathology occurs through amyloidogenic conformational templating. LPS was used as a control for potential inflammatory effects induced by αS (38)(39)(40). Forty to 90 d post IM injection (dpi) with hfib21-140 or mfib αS, M83 +/+ Tg mice developed a unilateral foot drop that progressed rapidly to a bilateral foot drop followed by full hind limb paralysis within a week of onset ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

Sacino¹,

Brooks²,

Thomas³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

289

343

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It has been hypothesized that α-synuclein (αS) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that αS pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of αS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) αS transgenic (Tg) mouse models. Within 2-3 mo after IM injection in αS homozygous M83 Tg mice and 3-4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS αS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed αS inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing αS CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of α-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive αS-induced neurodegeneration.amyloid | Parkinson disease S ynucleinopathies are a group of diseases defined by the presence of amyloidogenic α-synuclein (αS) inclusions that can occur in neurons and glia of the central nervous system (CNS) (1-4). In Parkinson disease (PD), a causative role for αS has been established via the discovery of mutations in the αS gene SNCA resulting in autosomal-dominant PD (4-11). Although αS inclusions (e.g., Lewy bodies) are the hallmark pathology of PD, how they contribute to disease pathogenesis remains controversial (1,3,4,12).Postmortem studies have suggested that αS pathology may spread following neuroanatomical tracts (13-15) and between cells (16-18). αS pathology has also been found in the peripheral nervous system (PNS): for example, in the enteric and pelvic plexus (19,20). And it has been suggested that αS pathology might originate in the nerves of the PNS and spread to the CNS (14). Experimentally, it has been reported that intracerebral injections of preformed amyloidogenic αS fibrils in nontransgenic (nTg) and αS transgenic (Tg) mice induce the formation of intracellular αS inclusions that appear to progress from the site of injection (21-26). Collectively, these studies support the notion that αS inclusion pathology may propagate via a prion-like conformational self-templating mechanism (27, 28). A caveat of the direct intracerebral injection of αS is tha...

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Section: Resultsmentioning

confidence: 99%

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

Sacino¹,

Brooks²,

Thomas³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

289

343

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“…Direct α-synuclein exposures to microglia cells have been described to activate many of the same responses (16). α-synuclein overexpression in the SNpc using recombinant adeno-associated virus (rAAV) has been previously found to produce a selective and relatively robust lesion of dopaminergic neurons, comparable to the level of neurodegeneration induced by LPS exposure (12,13).…”

Section: Resultsmentioning

confidence: 99%

Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

Daher

Volpicelli‐Daley

Blackburn

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

198

208

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Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease. Past studies have provided conflicting evidence for the protective effects of LRRK2 knockdown in models of Parkinson disease as well as other disorders. These discrepancies may be caused by uncertainty in the pathobiological mechanisms of LRRK2 action. Previously, we found that LRRK2 knockdown inhibited proinflammatory responses from cultured microglia cells. Here, we report LRRK2 knockout rats as resistant to dopaminergic neurodegeneration elicited by intracranial administration of LPS. Such resistance to dopaminergic neurodegeneration correlated with reduced proinflammatory myeloid cells recruited in the brain. Additionally, adeno-associated virus-mediated transduction of human α-synuclein also resulted in dopaminergic neurodegeneration in wild-type rats. In contrast, LRRK2 knockout animals had no significant loss of neurons and had reduced numbers of activated myeloid cells in the substantia nigra. Although LRRK2 expression in the wild-type rat midbrain remained undetected under nonpathological conditions, LRRK2 became highly expressed in inducible nitric oxide synthase (iNOS)-positive myeloid cells in the substantia nigra in response to α-synuclein overexpression or LPS exposures. Our data suggest that knocking down LRRK2 may protect from overt cell loss by inhibiting the recruitment of chronically activated proinflammatory myeloid cells. These results may provide value in the translation of LRRK2-targeting therapeutics to conditions where neuroinflammation may underlie aspects of neuronal dysfunction and degeneration.M issense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can be found in many families that transmit classical late-onset Parkinson disease (PD) from one generation to the next. Notably, these mutations are prevalent in the Ashkenazi Jewish and North African Arab Berber populations in more than 20% of PD cases (1, 2). Genome-wide association studies further provide evidence that links LRRK2 to PD susceptibility, with several risk alleles being identified in LRRK2 (3, 4). Association studies have also linked LRRK2 to Crohn disease and Hansen disease (5, 6). Although LRRK2 is widely considered an exciting target for therapeutic approaches in PD, the pathobiological role of LRRK2 as a critical modifier of disease susceptibility is not well understood. Additional insights into LRRK2-linked molecular pathways relevant to PD and neurodegeneration may enable more predictive preclinical studies.PD is pathologically characterized by both α-synuclein inclusions called Lewy bodies and Lewy neurites and the profound loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The absence of LRRK2 has been shown to impair α-synuclein inclusion formation, neuron loss, and microglia activation in mice overexpressing mutant α-synuclein (7). However, other studies that have crossed LRRK2 knockout mice with different α-synuclein transgenic mice did not observe robust protection fr...

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“…Other unconventional exocytosis mechanisms have been described for PrP (23) and ␣-synuclein (19). Endocytosis of monomeric A␤ (13, 14, 24 -26) and ␣-synuclein (15,(27)(28)(29) and endocytosis of the fibrillar and oligomeric states of some amyloids have also been reported. For instance, fibrilar A␤ can be cleared from the medium by microglia and astroglia (30 -32), whereas oligomeric A␤ can be taken up by neuroblastoma SH-SY5Y cells (33).…”

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confidence: 94%

Sequence-dependent Internalization of Aggregating Peptides

Couceiro

Gallardo

Smet

et al. 2015

Journal of Biological Chemistry

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Background: Prionoid propagation requires cell internalization of aggregated polypeptides. Results: Aggregates of different sequence are internalized through different endocytic pathways. Only phagocytosed aggregates (Ͼ1 m) elicit an HSF1-dependent proteostatic response. Conclusion: Proteostatic response upon aggregate internalization differs markedly depending on the sequence. Significance: The characterization of mechanisms of cell penetration is fundamental for the understanding of aggregate transmission in disease.

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Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia

Cited by 579 publications

References 62 publications

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

Sequence-dependent Internalization of Aggregating Peptides

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