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. 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.

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration

“…However, our data demonstrated that in rat brain 3R-tau isoforms are present yet at a much lower level (Müller et al, 1997;Gorath et al, 2001), which was later corroborated by Hanes et al (2009). In cultured oligodendrocytes tau protein is developmentally regulated and 4R-isoforms become more prominent, while 3R-isoforms decrease (Seiberlich et al, 2015). Tau mRNA is actively transported to the cellular processes Brought to you by | MIT Libraries Authenticated Download Date | 5/12/18 1:47 PM and particularly present in the primary processes (Gorath et al, 2001).…”

“…Cells failed to differentiate into MBPexpressing, sheet-forming, mature oligodendrocytes, and MTs were not as arborized and less bundled. Additionally, these cells were not capable to properly myelinate axons when cocultured with neurons derived from dorsal root ganglions of newborn rats ( Seiberlich et al, 2015). Hence a disturbance of the balance of tau leads to abnormalities in oligodendrocyte differentiation.…”

“…MTs were extremely thin and defects in the MT network were observed (Richter-Landsberg, 2008). Conversely, downregulation of tau by siRNA technique impaired process outgrowth and the transport of MBP mRNA to the cell periphery (Seiberlich et al, 2015). In tau-deficient cells MBP expression was diminished and the expression of the proteoglycan NG2 enhanced.…”

A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Periplaques of Spinal Cords from Progressive Multiple Sclerosis Patients

“…This finding appears of particular interest since, in oligodendrocytes , the translation of MBP and MOBP was previously shown to rely on specific mechanisms requiring a transport of the protein translation machinery (including ribosomal proteins) along the cell processes of oligodendrocytes [40][41][42][43][44][45]. To explore the existence of potential links between NDRG1 and the processes of translation/elongation, we performed a meta-analysis of NDRG1 protein interactants.…”

International Meeting Molecular Neurodegeneration: News and Views in Molecular Neuroscience in Health and Disease. Delmenhorst, Germany, July 20–22, 2015

“…Thus, tau is important for MBP mRNA transport and is 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 (Seiberlich et al 2015). The intricate neuro-glia interaction is dependent on intact molecular machineries including the cytoskeleton and the autophagy process and comparisons were made to further knowledge and translate into better disease management.…”