Key role of UBQLN2 in pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia

Abstract

Ubiquilin-2 (UBQLN2) is a member of the ubiquilin family, actively implicated in the degradation of misfolded and redundant proteins through the ubiquitin-proteasome system and macroautophagy. UBQLN2 received much attention after the discovery of gene mutations in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The abnormal presence of positive UBQLN2 inclusion in the cytosol of degenerating motor neurons of familial and sporadic forms of ALS patients has been newly related to neurodegeneration. Only recently, data have emerged on its role in liquid-liquid phase separation, in stress granule development and in the formation of secondary amyloid structures. Furthermore, several animal models are available to investigate its involvement in TDP-43 pathology and neuroinflammation in ALS. This review addresses the molecular pathogenetic pathways involving UBQLN2 abnormalities which are converging toward defects in clearance mechanisms. UBQLN2.

Keywords: Amyotrophic lateral sclerosis (ALS); Animal models; Autophagy; TAR DNA-binding protein 43 (TDP-43); Ubiquilin-2 (UBQLN2); Ubiquitin-proteasome system (UPS).

Fig. 1

Schematic representation of the domain architecture of the human Ubiquilin-2 gene. UBQLN2 gene is in the chromosome Xp11.21 and have only one coding exon. UBQLN2 possess a ubiquitin-like domain (UBL) domain on the N-terminal that interacts with the proteasome and a ubiquitin-associated domain (UBA) on the C-terminal required for the UPS activity. UBQLN2 gene also arbors four stress-induced protein 1 (STI-1)-like motif and a proline-rich repeat domain containing 12 PXX repeats. UBL: Ubiquitin-like domain; STI-1: Stress-induced protein 1; UBA: Ubiquitin-associated domain; HSP70: Heat-shock protein 70; Ub: Ubiquitin

Fig. 2

Roles of UBQLN2 in protein degradation in both the UPS and the autophagy systems. a UBQLN2 targets ubiquitinated substrates and interacts with ER proteins involved in endoplasmic-reticulum-associated protein degradation (ERAD), such as Herp and Ubxd8, to drive substrates degradation by the 26S proteasome. b UBQLN2 is also implicated in the macroautophagy and interacts with LC3 indirectly through an unknown mechanism and can deliver ubiquitinated proteins bound to the ubiquitin-associated domain (UBA). UBQLN2: Ubiquilin-2; Ub: Ubiquitin; LC3: Microtubule-associated protein 1 light chain 3, Herp: Homocysteine-induced endoplasmic reticulum protein, isoform A. Ubxd8: ubiquitin regulatory X domain-containing protein 8

Fig. 3

The integrative model for WT and mutant UBQLN2 pathology in ALS. WT UBQLN2 is prone to form oligomers with itself and associates with ubiquitinated substrates, chaperones and other molecules. WT UBQLN2 oligomers can assemble into membraneless organelles and form liquid-liquid phase separation droplets. The mechanism is UBQLN2 levels-dependant. Ubiquitin-binding can prevent this self-assembly and oligomerization of UBQLN2 and an increase of ubiquitin can remove the UBQLN2 LLPS formation. LLPS formations as well as oligomers of UBQLN2 can also become stress granules (SGs). The persistence of SGs can become aggregates or can lead to defect in RNA processing, leading to motor neurons death. Mutant UBQLN2 forms amyloid-like fibrillar aggregates, even in the absence of ubiquitin and chaperones. UBQLN2 mutation increase its insolubility and ubiquitin-binding. A reduced HSP70 binding and autophagy degradation can lead to the formation of aggregates. Aggregation is suspected to be driven by the UBA domain, while the UBL domain seems to inhibit aggregations. UBQLN2WT: Ubiquilin-2 wild-type; UBQLN2 Mut: Ubiquilin-2 mutants; LLPS: Liquid-liquid phase separation; FUS: Fused in sarcoma RNA-binding protein; TDP-43: TAR DNA-binding protein-encoding TDP-43; hnRNPAs: Heterogeneous nuclear ribonucleoprotein A