| 1. |
- Reyes, Juan, et al.
(författare)
-
Binding of alfa-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes
- 2019
-
Ingår i: Acta Neuropathologica. - : SPRINGER. - 0001-6322 .- 1432-0533. ; 138:1, s. 23-47
-
Tidskriftsartikel (refereegranskat)abstract
- The intercellular transfer of alpha-synuclein (-syn) has been implicated in the progression of Parkinson's disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of -syn oligomeric assemblies (o-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and o-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked o-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with -syn accumulation. Notably, we could alsodemonstrate a direct interaction between -syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related -synucleinopathies.
|
|
| 2. |
- Sardar Sinha, Maitrayee, et al.
(författare)
-
Alzheimer's disease pathology propagation by exosomes containing toxic amyloid-beta oligomers
- 2018
-
Ingår i: Acta Neuropathologica. - : SPRINGER. - 0001-6322 .- 1432-0533. ; 136:1, s. 41-56
-
Tidskriftsartikel (refereegranskat)abstract
- The gradual deterioration of cognitive functions in Alzheimer's disease is paralleled by a hierarchical progression of amyloid-beta and tau brain pathology. Recent findings indicate that toxic oligomers of amyloid-beta may cause propagation of pathology in a prion-like manner, although the underlying mechanisms are incompletely understood. Here we show that small extracellular vesicles, exosomes, from Alzheimer patients' brains contain increased levels of amyloid-beta oligomers and can act as vehicles for the neuron-to-neuron transfer of such toxic species in recipient neurons in culture. Moreover, blocking the formation, secretion or uptake of exosomes was found to reduce both the spread of oligomers and the related toxicity. Taken together, our results imply that exosomes are centrally involved in Alzheimer's disease and that they could serve as targets for development of new diagnostic and therapeutic principles.
|
|
| 3. |
- van Thuijl, Hinke F., et al.
(författare)
-
Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment
- 2015
-
Ingår i: Acta Neuropathologica. - : Springer Verlag (Germany). - 0001-6322 .- 1432-0533. ; 129:4, s. 597-607
-
Tidskriftsartikel (refereegranskat)abstract
- Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-na less than ve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.
|
|
