Glia. 2015 Sep;63(9):1621-35. doi: 10.1002/glia.22832. Epub 2015 Apr 4.
Downregulation of the microtubule associated protein tau impairs process outgrowth and myelin basic protein mRNA transport in oligodendrocytes.
Abstract
Oligodendrocytes, the myelin forming cells of the CNS, are characterized by their numerous membranous extensions, which enwrap neuronal axons and form myelin
sheaths. During differentiation oligodendrocytes pass different
morphological stages, downregulate the expression of the proteoglycan
NG2, and acquire major myelin specific proteins, such as myelin basic proteins (MBP) and proteolipid protein (PLP).
MBP mRNA is transported in RNA granules along the microtubules (MTs) to the periphery and translated locally. MTs participate in the elaboration and stabilization of the myelin forming extensions and are essential for cellular sorting processes. Their dynamic properties are regulated by microtubule associated proteins (MAPs).
The MAP tau is present in oligodendrocytes and involved in the regulation and stabilization of the MT network. To further elucidate the functional significance of tau in oligodendrocytes, we have downregulated tau by siRNA technology and studied the effects on cell differentiation and neuron-glia contact formation. The data show that tau knockdown impairs process outgrowth and leads to a decrease in MBP expression.
Furthermore, MBP mRNA transport to distant cellular extensions is impaired and cells remain in the NG2 stage. In myelinating cocultures with dorsal root ganglion neurons, oligodendrocyte precursor cells after tau miR RNA lentiviral knockdown develop into NG2 positive cells with very long and thin processes, contacting axons loosely, but fail to form internodes. This demonstrates that tau is important for MBP mRNA transport and involved in process formation. The disturbance of the balance of tau leads to abnormalities in oligodendrocyte differentiation, neuron-glia contact formation and the early myelination process. KEYWORDS:
MBP mRNA is transported in RNA granules along the microtubules (MTs) to the periphery and translated locally. MTs participate in the elaboration and stabilization of the myelin forming extensions and are essential for cellular sorting processes. Their dynamic properties are regulated by microtubule associated proteins (MAPs).
The MAP tau is present in oligodendrocytes and involved in the regulation and stabilization of the MT network. To further elucidate the functional significance of tau in oligodendrocytes, we have downregulated tau by siRNA technology and studied the effects on cell differentiation and neuron-glia contact formation. The data show that tau knockdown impairs process outgrowth and leads to a decrease in MBP expression.
Furthermore, MBP mRNA transport to distant cellular extensions is impaired and cells remain in the NG2 stage. In myelinating cocultures with dorsal root ganglion neurons, oligodendrocyte precursor cells after tau miR RNA lentiviral knockdown develop into NG2 positive cells with very long and thin processes, contacting axons loosely, but fail to form internodes. This demonstrates that tau is important for MBP mRNA transport and involved in process formation. The disturbance of the balance of tau leads to abnormalities in oligodendrocyte differentiation, neuron-glia contact formation and the early myelination process. KEYWORDS:
Fyn kinase; NG2 cells; microtubule bundling; myelination; neuron-glia interaction; rat brain
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Biol Chem. 2016 Mar;397(3):185-94. doi: 10.1515/hsz-2015-0157.
Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration.
Oligodendrocytes
are dependent on an intact, dynamic microtubule (MT) network, which
participates in the elaboration and stabilization of myelin forming extensions, and is essential for cellular sorting processes. The microtubule-associated protein tau
is constituent of oligodendrocytes. During culture maturation it is
developmentally regulated and important for MT stability, MT formation
and intracellular trafficking. Downregulation of tau impairs process outgrowth and the transport of myelin basic protein (MBP) mRNA to the cell periphery. Cells fail to differentiate into MBP-expressing, sheet-forming oligodendrocytes. Tau-positive
inclusions originating in oligodendrocytes and white matter pathology
are prominent in frontotemporal dementias, such as Pick's disease,
progressive supranuclear palsy and corticobasal degeneration.
An impairment or overload of the proteolytic degradation systems, i.e. the ubiquitin proteasomal system and the lysosomal degradation pathway, has been connected to the formation of protein aggregates. Large protein aggregates are excluded from the proteasome and degraded by autophagy, which is a highly selective process and requires receptor proteins for ubiquitinated proteins, including histone deacetylase 6 (HDAC6). HDAC6 is present in oligodendrocytes, and α-tubulin and tau are substrates of HDAC6.
In this review our current knowledge of the role of tau and protein aggregate formation in oligodendrocyte cell culture systems is summarized.
An impairment or overload of the proteolytic degradation systems, i.e. the ubiquitin proteasomal system and the lysosomal degradation pathway, has been connected to the formation of protein aggregates. Large protein aggregates are excluded from the proteasome and degraded by autophagy, which is a highly selective process and requires receptor proteins for ubiquitinated proteins, including histone deacetylase 6 (HDAC6). HDAC6 is present in oligodendrocytes, and α-tubulin and tau are substrates of HDAC6.
In this review our current knowledge of the role of tau and protein aggregate formation in oligodendrocyte cell culture systems is summarized.
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