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

Laurence Renaud,Philippe Codron,Jean-Pierre Julien,Vincent Picher-Martel

doi:10.1186/s40478-019-0758-7

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disorder associated with degeneration of upper and lower motor neurons [55]
It is documented that UBQLN2 is acting on stress granules formation, on TAR DNA-binding protein 43 (TDP-43) mislocalization into cytoplasmic inclusions, on cellular clearance pathways and neuroinflammation
It would be of interest to study the relationship between levels of UBQLN2 and the proteasome dysfunction in sporadic ALS

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disorder associated with degeneration of upper and lower motor neurons [55]. ALS-linked mutations in UBQLN2 gene were found to be associated with dysfunction of autophagy [24], neuroinflammation [49, 50] and formation of stress granules (SGs) [9]. UBQLN2 was found to be colocalizing with TDP-43 in the spinal cord of sALS patients, making it a component of the neuronal inclusions in patients affected with the sporadic form of the disease, suggesting a central role for this protein in ALS pathology [12, 17].

Results

Conclusion