Mutant UBQLN2 P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats

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 UBQLN2 mutant was select...

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Bibliographic Details
Published in:Acta neuropathologica communications 2018-11, Vol.6 (1), p.122
Main Authors: Chen, Tianhong, Huang, Bo, Shi, Xinglong, Gao, Limo, Huang, Cao
Format: Article
Language:English
Subjects:
Administration, Oral
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - pathology
Amyotrophic Lateral Sclerosis - physiopathology
Animals
Autophagy - genetics
Choline O-Acetyltransferase - metabolism
Disease Models, Animal
DNA-Binding Proteins - metabolism
Doxycycline - administration & dosage
Gene Expression Regulation - genetics
Histidine - genetics
Lysosomal-Associated Membrane Protein 2 - metabolism
Motor Disorders - etiology
Motor Neurons - metabolism
Motor Neurons - pathology
Motor Neurons - ultrastructure
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Mutation - genetics
Proline - genetics
Psychomotor Performance - physiology
Rats
Rats, Transgenic
Spinal Cord - pathology
Ubiquitins - genetics
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Summary: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 UBQLN2 mutant was selectively expressed in either the spinal motor neurons or astrocytes in rats. We found that selectively expressing mutant UBQLN2 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 UBQLN2 accumulation was associated with an age-dependent decrease in several core autophagy-related proteins. ALS-like phenotypes were not observed when mutant UBQLN2 was overexpressed in the astrocytes, however, even though the expression of the mutant UBQLN2 protein was higher in these rats. Our results suggest that selectively expressing mutant UBQLN2 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.
ISSN:2051-5960