Plectin in the Central Nervous System and a Putative Role in Brain Astrocytes

Abstract

Plectin, a high-molecular-mass cytolinker, is abundantly expressed in the central nervous system (CNS). Currently, a limited amount of data about plectin in the CNS prevents us from seeing the complete picture of how plectin affects the functioning of the CNS as a whole. Yet, by analogy to its role in other tissues, it is anticipated that, in the CNS, plectin also functions as the key cytoskeleton interlinking molecule. Thus, it is likely involved in signalling processes, thereby affecting numerous fundamental functions in the brain and spinal cord. Versatile direct and indirect interactions of plectin with cytoskeletal filaments and enzymes in the cells of the CNS in normal physiological and in pathologic conditions remain to be fully addressed. Several pathologies of the CNS related to plectin have been discovered in patients with plectinopathies. However, in view of plectin as an integrator of a cohesive mesh of cellular proteins, it is important that the role of plectin is also considered in other CNS pathologies. This review summarizes the current knowledge of plectin in the CNS, focusing on plectin isoforms that have been detected in the CNS, along with its expression profile and distribution alongside diverse cytoskeleton filaments in CNS cell types. Considering that the bidirectional communication between neurons and glial cells, especially astrocytes, is crucial for proper functioning of the CNS, we place particular emphasis on the known roles of plectin in neurons, and we propose possible roles of plectin in astrocytes.

Keywords: actin filaments; astrocytes; central nervous system; cytolinker proteins; glia; intermediate filaments; microtubules; neurons; plectin.

Figure 1

Schematic representation of plectin and its transcripts generated by alternative splicing of the 5’ end of the plectin gene PLEC. (A) The panel highlights interaction sites of cytoskeleton proteins and/or their associated proteins in astrocytes and neurons with their respective plectin domains. The C-terminal domain consists of six plectin repeat domains (PRD). (p), predicted interaction sites of certain IFs with plectin in astrocytes and neurons. Numbers above the schematic of plectin denote exons. ABD, actin binding domain. (B) Transcripts that give rise to individual plectin isoforms differ from each other only in short sequences at the 5’ end of the plectin gene. The numbers above the schematic denote consequent exons until exon 6. Exons 7 to 32 are not shown, as they are conserved among isoforms [4]. Individual exons are indicated by light and dark blue boxes, representing noncoding and coding regions, respectively. Red boxes denote two optionally spliced exons; 2α is inserted between exons 2 and 3, while 3α is inserted between exons 3 and 4.

Figure 2

Expression of plectin in various cells types in the brain. The figure depicts plectin-expressing cells in the cerebrum (A) and cerebellum (B). (A), Particularly the abundant expression of plectin (dark brown) is a trait of cells such as astrocytes, endothelial cells, and ependymal cells at the boundaries between brain parenchyma and fluid-filled compartments; for example, arteries, capillaries, and ventricles. Besides cells at the border of the parenchyma and fluid-filled parts of the brain, neurons, oligodendrocytes, and intermittently microglia also express plectin. (B), In the cerebellum, Bergmann glia in the molecular layer (ML) and astrocytes in the granule cell layer (GCL) also express plectin; however, plectin was not detected in Purkinje cells from rat cerebellum [23]. The abundance of plectin expression in each particular cell type is denoted by the colour intensity, according to the colour scales at the bottom of each panel. PCL, Purkinje cell layer.

Figure 3

Putative roles of plectin in astrocytes. The figure depicts an astrocyte, a type of glial cell that, on the one hand, together with the pre- and postsynaptic membrane constitute the so-called tripartite synapse (depicted at the top of the figure), and on other hand, enwrap brain capillaries (indicated at the bottom of the figure). Presumed roles of plectin in astrocytes are summarized around the astrocyte. Based on today’s knowledge of plectin, derived from other cell types and biochemical studies, and cytoskeleton elements in the CNS, we propose that plectin plays crucial roles in a number of intracellular processes of astrocytes, which are also related to the functioning of other brain cells, such as endothelial cells and neurons. By affecting tissue morphology and physiology, plectin in astrocytes may have a prominent impact on higher order functions of the CNS, such as learning and memory formation. Inset: image of a mouse astrocyte in culture with immunolabelled plectin (green labelling) and DAPI-labelled cell nucleus (in blue). Note that the plectin signal results in a pronounced filamentous distribution, which likely denotes binding to the cytoskeleton.