The Emerging Role of the RNA-Binding Protein SFPQ in Neuronal Function and Neurodegeneration

Abstract

RNA-binding proteins (RBPs) are a class of proteins known for their diverse roles in RNA biogenesis, from regulating transcriptional processes in the nucleus to facilitating translation in the cytoplasm. With higher demand for RNA metabolism in the nervous system, RBP misregulation has been linked to a wide range of neurological and neurodegenerative diseases. One of the emerging RBPs implicated in neuronal function and neurodegeneration is splicing factor proline- and glutamine-rich (SFPQ). SFPQ is a ubiquitous and abundant RBP that plays multiple regulatory roles in the nucleus such as paraspeckle formation, DNA damage repair, and various transcriptional regulation processes. An increasing number of studies have demonstrated the nuclear and also cytoplasmic roles of SFPQ in neurons, particularly in post-transcriptional regulation and RNA granule formation. Not surprisingly, the misregulation of SFPQ has been linked to pathological features shown by other neurodegenerative disease-associated RBPs such as aberrant RNA splicing, cytoplasmic mislocalization, and aggregation. In this review, we discuss recent findings on the roles of SFPQ with a particular focus on those in neuronal development and homeostasis as well as its implications in neurodegenerative diseases.

Keywords: DBHS protein family; Drosophila behavior human splicing; RNA-binding protein; SFPQ; cytoplasmic aggregation; neurodegenerative disease; nuclear protein; stress granules.

Figure 1

Crystal structures of human splicing factor proline- and glutamine-rich (SFPQ). (A) Schematic domain organization of human SFPQ (major isoform, SFPQ-A). The conserved Drosophila behavior/human splicing (DBHS) region consists of RNA-recognition motifs (RRM1 and RRM2), NonA/paraspeckles (NOPS) domain, and the coiled-coil domain, flanked by the N- and C-terminal low-complexity domains (LCDs). SFPQ has a DNA-binding domain (DBD) of which boundary remains to be defined. (B) Crystal structure of the dimerization domain of human SFPQ (PDB ID: 6NCQ) [9] with one monomer in the same color scheme in (A) and the other in grey. (C) Crystal structure of the full DBHS-region of the human SFPQ homodimer (PDB ID: 4WIJ) [7] with one monomer in the same color scheme in (A) and the other in grey. (D) Infinite polymer of SFPQ (PDB ID: 4WIJ) [7]. Polymerization of SFPQ mediated by the coiled-coil interaction motif is critical for the cellular function of SFPQ. (E) Zinc-mediated infinite polymerization of SFPQ (PDB ID: 6OWJ) that may represent a pathological form of polymerization under high zinc condition [10] (further discussion in Section 4.1). Zn(II) atoms are depicted as black spheres.

Figure 2

The nuclear function of SFPQ. SFPQ is critical for the structural integrity of paraspeckles (A). SFPQ interacts with other splicing factors such as hnRNP M and NeuN to regulate alternative splicing of pre-mRNA (B). SFPQ acts as an important transcriptional coactivator by interacting with RNA Polymerase II (C). SFPQ is also involved in DNA damage repair—both in homologous repair and nonhomologous end-joining pathways (D). SFPQ facilitates telomere maintenance, interacting with a telomere repeat-containing long noncoding RNA, TERRA (E). SFPQ is depicted as red circles labeled with “S” while its dimerization partner NONO as green circles with “N”.

Figure 3

Schematic comparison of the neuronal functions of SFPQ in physiological conditions (A–D) with pathological features of SFPQ in the disease states (a–d). (A) SFPQ is critical for transcriptional elongation of long genes in the developing brain while the cytoplasmic aggregation and mislocalization of SFPQ are observed in many neurodegenerative diseases including, amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer’s disease (AD). One possible mechanism of cytoplasmic aggregation and mislocalization of SFPQ caused by high zinc concentration in the cytosol is shown (a). (B) The alternative splicing of the NMHC II-B mRNA by NeuN and SFPQ in supporting neuronal development is influenced by TDP-43 mutation causing cytoplasmic mislocalization in the disease state (b). (C) Alternative splicing of the Mapt gene to form different isoforms of tau, is mediated by SFPQ and FUS; altered splicing is caused by mutation of either of these two RBPs (c). (D) SFPQ, TIA-1, and tau form reversible stress granules (SGs) under stress, which become persistent and pathological SGs in the disease state (d). SFPQ is depicted as red circles labeled with “S”