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 mut...
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| Format: | Article |
| Language: | English |
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BMC
2018-11-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-018-0627-9 |
| _version_ | 1818313608688304128 |
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| author | Tianhong Chen Bo Huang Xinglong Shi Limo Gao Cao Huang |
| author_facet | Tianhong Chen Bo Huang Xinglong Shi Limo Gao Cao Huang |
| author_sort | Tianhong Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T08:36:27Z |
| format | Article |
| id | doaj.art-b3261929ec6a4577a5879660a3a92f2b |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-13T08:36:27Z |
| publishDate | 2018-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-b3261929ec6a4577a5879660a3a92f2b2022-12-21T23:53:38ZengBMCActa Neuropathologica Communications2051-59602018-11-016111510.1186/s40478-018-0627-9Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in ratsTianhong Chen0Bo Huang1Xinglong Shi2Limo Gao3Cao Huang4Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson UniversityLaboratory Animal Center, Shanxi Provincial People’s HospitalDepartment of Pathology, Anatomy & Cell Biology, Thomas Jefferson UniversityDepartment of Ophthalmology, The Third Xiangya Hospital of Central South UniversityDepartment of Pathology, Anatomy & Cell Biology, Thomas Jefferson UniversityAbstract 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.http://link.springer.com/article/10.1186/s40478-018-0627-9Amyotrophic lateral sclerosisALSUBQLN2P62Motor neuron degenerationAutophagy |
| spellingShingle | Tianhong Chen Bo Huang Xinglong Shi Limo Gao Cao Huang Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats Acta Neuropathologica Communications Amyotrophic lateral sclerosis ALS UBQLN2 P62 Motor neuron degeneration Autophagy |
| title | Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats |
| title_full | Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats |
| title_fullStr | Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats |
| title_full_unstemmed | Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats |
| title_short | Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats |
| title_sort | mutant ubqln2p497h in motor neurons leads to als like phenotypes and defective autophagy in rats |
| topic | Amyotrophic lateral sclerosis ALS UBQLN2 P62 Motor neuron degeneration Autophagy |
| url | http://link.springer.com/article/10.1186/s40478-018-0627-9 |
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