Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats

Abstract

Mutations in ubiquilin2 (UBQLN2) have been linked to abnormal protein aggregation in amyotrophic lateral sclerosis (ALS). The mechanisms underlying UBQLN2-related neurodegenerative diseases remain unclear. Using a tetracycline-regulated gene expression system, the ALS-linked UBQLN2P497H mutant was selectively expressed in either the spinal motor neurons or astrocytes in rats. We found that selectively expressing mutant UBQLN2P497H in the spinal motor neurons caused several core features of ALS, including the progressive degeneration of motor neurons, the denervation atrophy of skeletal muscles, and the abnormal protein accumulation. Furthermore, mutant UBQLN2P497H accumulation was associated with an age-dependent decrease in several core autophagy-related proteins. ALS-like phenotypes were not observed when mutant UBQLN2P497H was overexpressed in the astrocytes, however, even though the expression of the mutant UBQLN2P497H protein was higher in these rats. Our results suggest that selectively expressing mutant UBQLN2P497H in motor neurons is sufficient to trigger the development of ALS in rats. Our results further indicate that the compromised autophagy-lysosomal pathway plays a critical role in the pathogenesis of UBQLN2-related neurodegenerative diseases.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0627-9) contains supplementary material, which is available to authorized users.

Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins

“…All three brain-expressed ubiquilins contain a C-terminal ubiquitin-associated (UBA) domain, an N-terminal ubiquitin-like (UBL) domain and four stress-induced protein-like (STI) domains that mediate binding to molecular chaperones. The most well-characterized function for ubiquilins is as ubiquitin-proteasome shuttle factors 6,7 , but they have been implicated in other protein homeostasis pathways including autophagy and endoplasmic reticulumassociated protein degradation (ERAD) [8][9][10][11][12] .…”

Mendelian neurodegenerative disease genes involved in autophagy

“…Mutations of UBQLN2 gene are found in cases of familial ALS and ALS-FTD 135 and the majority reside within its proline-rich domain that is important for protein-protein interactions 139 . Expression of the ALSassociated UBQLN2 P497H mutation in flies results in impaired autophagic degradation, due to a failure in lysosomal acidification 138 , whereas rat spinal motor neurons expressing the UBQLN2 P497H mutation have decreased LC3 lipidation 140 . Interestingly, expression of the P497H or P506T ALS-associated UBQLN2 mutations in human neuroblastoma cells leads to a deficiency in protein degradation through the proteasome system 139 .…”

Autophagy in Neurodegenerative Diseases: A Hunter for Aggregates

“…Loss of UBQLN2 was shown to increase ubiquitinated TDP-43 levels and impair autophagic degradation by promoting the fragmentation of lysosomal v-ATPase [89,206]. The overexpression of an ALS-associated UBQLN2 mutant, such as P497H, caused the formation of UBQLN2 inclusions bearing p62 and the accumulation of ubiquitinated-protein aggregates, resulting in defective autophagy and ALS-like phenotypes [85,86,207].…”