Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells

Ettle, Benjamin; Reiprich, Simone; Deusser, Janina; Schlachetzki, J; Xiang, Wei; Prots, Iryna; Masliah, Eliezer; Winner, Beate; Wegner, Michael

doi:10.1016/j.mcn.2014.06.012

Cited by 42 publications

(62 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After ceasing aSyn expression due to reduced activity of the lentiviral EF1a promoter, the maturation potential of SYN-OPCs was restored to control levels indicating that the intracellular level of aSyn is a crucial determinant of OPC maturation. Matching these results, primary OPC differentiation was impaired after uptake of recombinant aSyn and restored upon reduction of intracellular aSyn levels [2] . In summary, our studies using human post-mortem MSA tissue as well as pre-clinical in vitro and in vivo models reveal an additional pathological feature of MSA [1,2] .…”

Section: Research Highlightsupporting

confidence: 54%

“…We recently addressed the role of OPCs in MSA by investigating human post-mortem tissue as well as pre-clinical animal and cell culture models for MSA [1,2] . Intriguingly, we observed increased numbers of striatal platelet-derived growth factor receptor-alpha (PDGFRa)-positive OPCs in MSA patients suggesting a proliferative reaction of OPCs in response to demyelination in MSA [1] .…”

Section: Research Highlightmentioning

confidence: 99%

“…Using a complementary in vitro model to study oligodendroglial maturation, we transduced primary OPCs derived from neonatal rats with lentiviral vectors enabling aSyn expression driven by the elongation factor 1-alpha (EF1a) promoter [2] . Analyzing OPC maturation during a 6 day differentiation paradigm, aSyn expressing OPCs (SYN-OPCs) robustly showed a delayed onset of maturation evident by increased levels of PDGFRa and decreased levels of myelin proteins, i.e.…”

Section: Research Highlightmentioning

confidence: 99%

“…Both stable aSyn expressing OPC-like central glia-4 (CG4) cells [1] and transiently aSyn expressing primary OPCs derived from neonatal rats [2] robustly showed a severely reduced maturation. Similarly, primary OPCs exhibit a delayed maturation upon uptake of recombinant aSyn [2] . Taken together, our findings indicate that OPC dysfunction is a pathological feature of MSA.…”

mentioning

confidence: 99%

“…Observing aSyn-positive OPCs in MSA patients, we additionally established two independent in vitro models in order to explore the effect of intracellular aSyn on OPC maturation. Both stable aSyn expressing OPC-like central glia-4 (CG4) cells [1] and transiently aSyn expressing primary OPCs derived from neonatal rats [2] robustly showed a severely reduced maturation. Similarly, primary OPCs exhibit a delayed maturation upon uptake of recombinant aSyn [2] .…”

mentioning

confidence: 99%

See 4 more Smart Citations

Promoting oligodendrocyte progenitor cell maturation and remyelination as a novel therapeutical approach for multiple system atrophy

Ettle

Schlachetzki

2015

Ther Targets Neurol Dis

View full text Add to dashboard Cite

Alpha-synuclein (aSyn) aggregation within mature oligodendrocytes is the characteristic neuropathological feature of multiple system atrophy (MSA). In fact, dysfunction of oligodendrocytes is considered as a primary event in MSA pathogenesis leading to myelin loss and, ultimately, reduced axonal integrity and neuronal cell loss. Oligodendrocyte progenitor cells (OPCs) are widely distributed in the adult central nervous system and represent a potential endogenous source for replacement of such dysfunctional oligodendrocytes. The extent to which OPCs are affected in MSA or even contribute to MSA pathogenesis remains undefined. Thus, we analyzed OPCs post-mortem in MSA brains and in a pre-clinical MSA mouse model expressing aSyn under the myelin basic protein (MBP) promoter. Importantly, we detected elevated numbers of striatal OPCs in MSA and its model [1] . Observing aSyn-positive OPCs in MSA patients, we additionally established two independent in vitro models in order to explore the effect of intracellular aSyn on OPC maturation. Both stable aSyn expressing OPC-like central glia-4 (CG4) cells [1] and transiently aSyn expressing primary OPCs derived from neonatal rats [2] robustly showed a severely reduced maturation. Similarly, primary OPCs exhibit a delayed maturation upon uptake of recombinant aSyn [2] . Taken together, our findings indicate that OPC dysfunction is a pathological feature of MSA. In addition, promoting OPC differentiation may represent a novel and promising interventional strategy for therapeutic approaches in MSA.

show abstract

Section: Research Highlightsupporting

confidence: 54%

Section: Research Highlightmentioning

confidence: 99%

Section: Research Highlightmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Promoting oligodendrocyte progenitor cell maturation and remyelination as a novel therapeutical approach for multiple system atrophy

Ettle

Schlachetzki

2015

Ther Targets Neurol Dis

View full text Add to dashboard Cite

show abstract

Anti‐LINGO‐1 antibody treatment alleviates cognitive deficits and promotes maturation of oligodendrocytes in the hippocampus of APP/PS1 mice

Yang

Jiang

Zhang

et al. 2022

J of Comparative Neurology

View full text Add to dashboard Cite

Leucine‐rich repeat and immunoglobulin‐like domain‐containing nogo receptor‐interacting protein 1 (LINGO‐1), a negative regulator of oligodendrocyte differentiation and myelination, is associated with cognitive function, and its expression is highly upregulated in Alzheimer's disease (AD) patients. Anti‐LINGO‐1 antibody treatment can effectively antagonize the negative regulatory effect of LINGO‐1. In this study, we aim to assess the effect of anti‐LINGO‐1 antibody treatment on cognition and hippocampal oligodendrocytes in an AD transgenic animal model. First, 10‐month‐old male amyloid‐β (Aβ) protein precursor (APP)/presenilin 1 (PS1) mice were administered anti‐LINGO‐1 antibody for 8 weeks. Then, learning and memory abilities were assessed with the Morris water maze (MWM) and Y‐maze tests, and Aβ deposition and hippocampal oligodendrocytes were investigated by immunohistochemistry, immunofluorescence, and stereology. We found that anti‐LINGO‐1 antibody alleviated the deficits in spatial learning and memory abilities and working and reference memory abilities, decreased the density of LINGO‐1 positive cells, decreased Aβ deposition, significantly increased the number of mature oligodendrocytes and the density of myelin, reversed the abnormal increases in the number of oligodendrocyte lineage cells and the densities of oligodendrocytes precursor cells in APP/PS1 mice. Our results provide evidence that LINGO‐1 might be involved in the process of oligodendrocyte dysmaturity in the hippocampus of AD mice, and that antagonizing LINGO‐1 can alleviate cognitive deficits in APP/PS1 mice and decrease Aβ deposition and promote oligodendrocyte differentiation and maturation in the hippocampus of these mice. Our findings suggest that changes in LINGO‐1 and oligodendrocytes in the hippocampus play important roles in the pathogenesis of AD and that antagonizing LINGO‐1 might be a potential therapeutic strategy for AD.

show abstract

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

et al. 2016

Self Cite

View full text Add to dashboard Cite

Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic α-synuclein on the formation of myelin sheaths in order to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic α-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of α-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel α-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic α-synuclein. Additionally, benztropine restored the α-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the α-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.

show abstract

Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells

Cited by 42 publications

References 52 publications

Promoting oligodendrocyte progenitor cell maturation and remyelination as a novel therapeutical approach for multiple system atrophy

Promoting oligodendrocyte progenitor cell maturation and remyelination as a novel therapeutical approach for multiple system atrophy

Anti‐LINGO‐1 antibody treatment alleviates cognitive deficits and promotes maturation of oligodendrocytes in the hippocampus of APP/PS1 mice

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

Contact Info

Product

Resources

About