Nervous system functions are established by the coordinate interaction of nerve cells and glia, which might be impaired during aging and in neurodegenerative disorders. Our research is centered around oligodendrocytes, the myelin forming cells of the central nervous system, with a major focus on biochemical changes and molecular mechanisms regulating developmental processes, cell differentiation, cell survival, and cell death. At present the following major research areas are pursued:

Mature oligodendrocytes in culture are characterized by their numerous cytoplasmic extensions and flat membranous sheets. These sheets contain an extensive cytoskeletal network of microtubules (MTs) and microfilaments. Microtubules participate in the elaboration and stabilization of the myelin-containing cellular processes, intracellular sorting processes, and provide the rails for organelle trafficking. These rails are especially important to guide mitochondria to the cytoplasmic extensions. In oligodendrocytes, the predominant microtubule-associated proteins (MAPs) are MAP2 and tau, which might be involved in the regulation and stabilization of the dynamic MT network.

Alterations or disruption of the cytoskeleton and filamentous proteinaceous cell inclusions in nerve cells and glia are frequent hallmarks of neurodegenerative diseases and might cause cell death and degeneration. Glial changes occur in a variety of diseases. Glial cytoplasmic inclusions (GCIs) and inclusion bodies, containing abnormal microtubular structures, which stain positively for stress proteins, MAPs and ubiquitin, are found in oligodendrocytes of the affected brains.

GCIs originating in oligodendrocytes are the histological hallmark of multiple system atrophy (MSA). MSA represents a progressive, sporadic neurological disorder with symptoms of Parkinsonism, ataxia and autonomic dysfunction. alpha-Synuclein is the major building block in GCIs but various reports demonstrate also the presence of tau. Emerging evidence indicates that tau and alpha-synuclein might overlap in the pathological features of inclusion body diseases, and possibly interact with and affect one another.

We have shown that oligodendrocytes express all six isoforms of the microtubule associated protein tau. Oligodendrocytes are particularly sensitive to oxidative and proteasomal stress, causing upregulation of heat shock proteins and modulation of tau phosphorylation through the activation of protein phosphatase PP2A. Proteasomal inhibition causes the appearance of tau-positive fibrillary protein aggregates in oligodendrocytes. These also contain heat shock proteins and ubiquitin, and thus resemble glial cell inclusion bodies, as observed in frontotemporal dementias, e.g Progressive supranuclear palsy (PSP) and Corticobasal degeneration (CBD). Our recent work indicates that small heat shock proteins (HSP), mainly HSP25 and alphaB-crystallin associate with the cytoskeleton, contribute to survival responses and promote the solubility of tau in oligodendroglial cells. HSP32 might be a sensor of oxidative stress and is upregulated in oligodendrocytes during demyelinating processes.

Furthermore, we have developed an immortalized oligodendroglial cell line known as OLN-93. These we have engineered to express stably the longest human tau isoform with four microtubule binding repeats (OLN-t40) which is most prominent in tau inclusions in PSP, the shortest tau isoform with three MT-binding repeats (OLN-t44), or the longest tau isoform with the P301L mutation (OLN-P301L). This mutation has been linked to the formation of filamentous tau in oligodendrocytes, oligodendroglial apoptosis and the occurrence of 4-repeat hyperphosphorylated tau in transgenic mouse models. Using this cell line as a model system, we could demonstrate that proteasomal inhibition and tau hyperphosphorylation, exerted through okadaic acid, contribute to the formation of inclusion bodies. Also, proteasomal inhibition causes aggresome formation, which is accompanied by mitochondrial redistribution and cytoskeletal reorganization.
More recently we have engineered OLN cell lines coexpressing tau and alpha-synuclein which are used to study the molecular mechanisms underlying the aggregation process of these proteins.