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Article ; Online: Neuronal Puncta/Aggregate Formation by WT and Mutant UBQLN2.

Safren, Nathaniel / Sharkey, Lisa M / Barmada, Sami J

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2551, Page(s) 561–573

Abstract: Protein aggregates are a common feature of nearly all neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Here we describe a method to quickly and accurately measure protein aggregation ...

Abstract	Protein aggregates are a common feature of nearly all neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Here we describe a method to quickly and accurately measure protein aggregation in cells expressing a fluorescently tagged aggregation-prone protein. This unbiased method obviates the need for manual scoring and facilitates the identification of factors governing protein self-assembly and its downstream consequences for cell heath.
MeSH term(s)	Humans ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Neurons/metabolism ; Protein Aggregates ; Neurodegenerative Diseases/metabolism ; Parkinson Disease/metabolism ; Autophagy-Related Proteins/genetics ; Autophagy-Related Proteins/metabolism ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism
Chemical Substances	Protein Aggregates ; UBQLN2 protein, human ; Autophagy-Related Proteins ; Adaptor Proteins, Signal Transducing
Language	English
Publishing date	2022-09-28
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2597-2_34
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Article ; Online: Pathogenic mutations in UBQLN2 exhibit diverse aggregation propensity and neurotoxicity.

Safren, Nathaniel / Dao, Thuy P / Mohan, Harihar Milaganur / Huang, Camellia / Trotter, Bryce / Castañeda, Carlos A / Paulson, Henry / Barmada, Sami / Sharkey, Lisa M

Scientific reports

2024 Volume 14, Issue 1, Page(s) 6049

Abstract: The ubiquitin-adaptor protein UBQLN2 promotes degradation of several aggregate-prone proteins implicated in neurodegenerative diseases. Missense UBQLN2 mutations also cause X-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ... ...

Abstract	The ubiquitin-adaptor protein UBQLN2 promotes degradation of several aggregate-prone proteins implicated in neurodegenerative diseases. Missense UBQLN2 mutations also cause X-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previously we demonstrated that the liquid-like properties of UBQLN2 molecular assemblies are altered by a specific pathogenic mutation, P506T, and that the propensity of UBQLN2 to aggregate correlated with neurotoxicity. Here, we systematically assess the effects of multiple, spatially distinct ALS/FTD-linked missense mutations on UBQLN2 aggregation propensity, neurotoxicity, phase separation, and autophagic flux. In contrast to what we observed for the P506T mutation, no other tested pathogenic mutant exhibited a clear correlation between aggregation propensity and neurotoxicity. These results emphasize the unique nature of pathogenic UBQLN2 mutations and argue against a generalizable link between aggregation propensity and neurodegeneration in UBQLN2-linked ALS/FTD.
MeSH term(s)	Humans ; Frontotemporal Dementia/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Autophagy-Related Proteins/genetics ; Mutation ; Adaptor Proteins, Signal Transducing/metabolism
Chemical Substances	Autophagy-Related Proteins ; Adaptor Proteins, Signal Transducing ; UBQLN2 protein, human
Language	English
Publishing date	2024-03-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-55582-9
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Article ; Online: Monitoring Neuronal Survival via Longitudinal Fluorescence Microscopy.

Weskamp, Kaitlin / Safren, Nathaniel / Miguez, Roberto / Barmada, Sami

Journal of visualized experiments : JoVE

2019 , Issue 143

Abstract: Standard cytotoxicity assays, which require the collection of lysates or fixed cells at multiple time points, have limited sensitivity and capacity to assess factors that influence neuronal fate. These assays require the observation of separate ... ...

Abstract	Standard cytotoxicity assays, which require the collection of lysates or fixed cells at multiple time points, have limited sensitivity and capacity to assess factors that influence neuronal fate. These assays require the observation of separate populations of cells at discrete time points. As a result, individual cells cannot be followed prospectively over time, severely limiting the ability to discriminate whether subcellular events, such as puncta formation or protein mislocalization, are pathogenic drivers of disease, homeostatic responses, or merely coincidental phenomena. Single-cell longitudinal microscopy overcomes these limitations, allowing the researcher to determine differences in survival between populations and draw causal relationships with enhanced sensitivity. This video guide will outline a representative workflow for experiments measuring single-cell survival of rat primary cortical neurons expressing a fluorescent protein marker. The viewer will learn how to achieve high-efficiency transfections, collect and process images enabling the prospective tracking of individual cells, and compare the relative survival of neuronal populations using Cox proportional hazards analysis.
MeSH term(s)	Animals ; Cell Death ; Cell Survival ; Cerebral Cortex/cytology ; Microscopy, Fluorescence/methods ; Neurons/cytology ; Neurons/metabolism ; Proportional Hazards Models ; Rats, Long-Evans
Language	English
Publishing date	2019-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/59036
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Article: Monitoring neuronal survival via longitudinal fluorescence microscopy

Weskamp, Kaitlin / Safren, Nathaniel / Miguez, Roberto / Barmada, Sami

Journal of visualized experiments. 2019 Jan. 19, , no. 143

2019

Abstract	Standard cytotoxicity assays, which require the collection of lysates or fixed cells at multiple time points, have limited sensitivity and capacity to assess factors that influence neuronal fate. These assays require the observation of separate populations of cells at discrete time points. As a result, individual cells cannot be followed prospectively over time, severely limiting the ability to discriminate whether subcellular events, such as puncta formation or protein mislocalization, are pathogenic drivers of disease, homeostatic responses, or merely coincidental phenomena. Single-cell longitudinal microscopy overcomes these limitations, allowing the researcher to determine differences in survival between populations and draw causal relationships with enhanced sensitivity. This video guide will outline a representative workflow for experiments measuring single-cell survival of rat primary cortical neurons expressing a fluorescent protein marker. The viewer will learn how to achieve high-efficiency transfections, collect and process images enabling the prospective tracking of individual cells, and compare the relative survival of neuronal populations using Cox proportional hazards analysis.
Keywords	fluorescence microscopy ; fluorescent proteins ; monitoring ; neurons ; rats ; toxicity testing
Language	English
Dates of publication	2019-0119
Size	p. e59036.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/59036
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Article ; Online: Development of a specific live-cell assay for native autophagic flux.

Safren, Nathaniel / Tank, Elizabeth M / Malik, Ahmed M / Chua, Jason P / Santoro, Nicholas / Barmada, Sami J

The Journal of biological chemistry

2021 Volume 297, Issue 3, Page(s) 101003

Abstract: Autophagy is an evolutionarily conserved pathway mediating the breakdown of cellular proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction contributes to many diseases; nevertheless, development of effective autophagy modulating ... ...

Abstract	Autophagy is an evolutionarily conserved pathway mediating the breakdown of cellular proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction contributes to many diseases; nevertheless, development of effective autophagy modulating drugs is hampered by fundamental deficiencies in available methods for measuring autophagic activity or flux. To overcome these limitations, we introduced the photoconvertible protein Dendra2 into the MAP1LC3B locus of human cells via CRISPR/Cas9 genome editing, enabling accurate and sensitive assessments of autophagy in living cells by optical pulse labeling. We used this assay to perform high-throughput drug screens of four chemical libraries comprising over 30,000 diverse compounds, identifying several clinically relevant drugs and novel autophagy modulators. A select series of candidate compounds also modulated autophagy flux in human motor neurons modified by CRISPR/Cas9 to express GFP-labeled LC3. Using automated microscopy, we tested the therapeutic potential of autophagy induction in several distinct neuronal models of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In doing so, we found that autophagy induction exhibited discordant effects, improving survival in disease models involving the RNA binding protein TDP-43, while exacerbating toxicity in neurons expressing mutant forms of UBQLN2 and C9ORF72 associated with familial ALS/FTD. These studies confirm the utility of the Dendra2-LC3 assay, while illustrating the contradictory effects of autophagy induction in different ALS/FTD subtypes.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/therapy ; Autophagy/drug effects ; Autophagy-Related Proteins/genetics ; C9orf72 Protein/genetics ; CRISPR-Cas Systems ; DNA-Binding Proteins/genetics ; Drug Screening Assays, Antitumor ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/therapy ; HEK293 Cells ; High-Throughput Screening Assays ; Humans ; Luminescent Proteins/genetics ; Microtubule-Associated Proteins/genetics ; Models, Biological ; Motor Neurons/metabolism ; Mutation
Chemical Substances	Adaptor Proteins, Signal Transducing ; Autophagy-Related Proteins ; C9orf72 Protein ; C9orf72 protein, human ; DNA-Binding Proteins ; Dendra2 protein, Dendronephthya ; Luminescent Proteins ; MAP1LC3B protein, human ; Microtubule-Associated Proteins ; TARDBP protein, human ; UBQLN2 protein, human
Language	English
Publishing date	2021-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2021.101003
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Article ; Online: RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control.

Mohan, Harihar Milaganur / Trzeciakiewicz, Hanna / Pithadia, Amit / Crowley, Emily V / Pacitto, Regina / Safren, Nathaniel / Trotter, Bryce / Zhang, Chengxin / Zhou, Xiaogen / Zhang, Yang / Basrur, Venkatesha / Paulson, Henry L / Sharkey, Lisa M

Cellular and molecular life sciences : CMLS

2022 Volume 79, Issue 3, Page(s) 176

Abstract: The brain-expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been ... ...

Abstract	The brain-expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been implicated in numerous neurodegenerative diseases including ALS/FTD. UBQLN2 typically resides in the cytoplasm but in disease can translocate to the nucleus, as in Huntington's disease where it promotes the clearance of mutant Huntingtin. How UBQLN2 translocates to the nucleus and clears aberrant nuclear proteins, however, is not well understood. In a mass spectrometry screen to discover UBQLN2 interactors, we identified a family of small (13 kDa), highly homologous uncharacterized proteins, RTL8, and confirmed the interaction between UBQLN2 and RTL8 both in vitro using recombinant proteins and in vivo using mouse brain tissue. Under endogenous and overexpressed conditions, RTL8 localizes to nucleoli. When co-expressed with UBQLN2, RTL8 promotes nuclear translocation of UBQLN2. RTL8 also facilitates UBQLN2's nuclear translocation during heat shock. UBQLN2 and RTL8 colocalize within ubiquitin-enriched subnuclear structures containing PQC components. The robust effect of RTL8 on the nuclear translocation and subnuclear localization of UBQLN2 does not extend to the other brain-expressed ubiquilins, UBQLN1 and UBQLN4. Moreover, compared to UBQLN1 and UBQLN4, UBQLN2 preferentially stabilizes RTL8 levels in human cell lines and in mouse brain, supporting functional heterogeneity among UBQLNs. As a novel UBQLN2 interactor that recruits UBQLN2 to specific nuclear compartments, RTL8 may regulate UBQLN2 function in nuclear protein quality control.
MeSH term(s)	Adaptor Proteins, Signal Transducing/deficiency ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Amino Acid Sequence ; Animals ; Autophagy-Related Proteins/deficiency ; Autophagy-Related Proteins/genetics ; Autophagy-Related Proteins/metabolism ; Brain/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Nucleolus/metabolism ; HEK293 Cells ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Knockout ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Protein Binding ; Protein Isoforms/chemistry ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/isolation & purification ; Sequence Alignment ; Temperature ; Ubiquitin/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Autophagy-Related Proteins ; Carrier Proteins ; Membrane Proteins ; Nuclear Proteins ; Protein Isoforms ; RTL8C protein, human ; Recombinant Proteins ; UBQLN1 protein, human ; UBQLN1 protein, mouse ; UBQLN2 protein, human ; UBQLN4 protein, human ; Ubiquitin
Language	English
Publishing date	2022-03-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04170-z
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Article: RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control

Mohan, Harihar Milaganur / Trzeciakiewicz, Hanna / Pithadia, Amit / Crowley, Emily V. / Pacitto, Regina / Safren, Nathaniel / Trotter, Bryce / Zhang, Chengxin / Zhou, Xiaogen / Zhang, Yang / Basrur, Venkatesha / Paulson, Henry L. / Sharkey, Lisa M.

Cellular and molecular life sciences. 2022 Mar., v. 79, no. 3

2022

Abstract	The brain-expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been implicated in numerous neurodegenerative diseases including ALS/FTD. UBQLN2 typically resides in the cytoplasm but in disease can translocate to the nucleus, as in Huntington’s disease where it promotes the clearance of mutant Huntingtin. How UBQLN2 translocates to the nucleus and clears aberrant nuclear proteins, however, is not well understood. In a mass spectrometry screen to discover UBQLN2 interactors, we identified a family of small (13 kDa), highly homologous uncharacterized proteins, RTL8, and confirmed the interaction between UBQLN2 and RTL8 both in vitro using recombinant proteins and in vivo using mouse brain tissue. Under endogenous and overexpressed conditions, RTL8 localizes to nucleoli. When co-expressed with UBQLN2, RTL8 promotes nuclear translocation of UBQLN2. RTL8 also facilitates UBQLN2’s nuclear translocation during heat shock. UBQLN2 and RTL8 colocalize within ubiquitin-enriched subnuclear structures containing PQC components. The robust effect of RTL8 on the nuclear translocation and subnuclear localization of UBQLN2 does not extend to the other brain-expressed ubiquilins, UBQLN1 and UBQLN4. Moreover, compared to UBQLN1 and UBQLN4, UBQLN2 preferentially stabilizes RTL8 levels in human cell lines and in mouse brain, supporting functional heterogeneity among UBQLNs. As a novel UBQLN2 interactor that recruits UBQLN2 to specific nuclear compartments, RTL8 may regulate UBQLN2 function in nuclear protein quality control.
Keywords	brain ; cytoplasm ; heat stress ; humans ; mass spectrometry ; mice ; mutants ; proteasome endopeptidase complex ; protein value ; quality control ; ubiquitin
Language	English
Dates of publication	2022-03
Size	p. 176.
Publishing place	Springer International Publishing
Document type	Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04170-z
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins.

Gerson, Julia E / Linton, Hunter / Xing, Jiazheng / Sutter, Alexandra B / Kakos, Fayth S / Ryou, Jaimie / Liggans, Nyjerus / Sharkey, Lisa M / Safren, Nathaniel / Paulson, Henry L / Ivanova, Magdalena I

Scientific reports

2021 Volume 11, Issue 1, Page(s) 287

Abstract: The brain-expressed ubiquilins, UBQLNs 1, 2 and 4, are highly homologous proteins that participate in multiple aspects of protein homeostasis and are implicated in neurodegenerative diseases. Studies have established that UBQLN2 forms liquid-like ... ...

Abstract	The brain-expressed ubiquilins, UBQLNs 1, 2 and 4, are highly homologous proteins that participate in multiple aspects of protein homeostasis and are implicated in neurodegenerative diseases. Studies have established that UBQLN2 forms liquid-like condensates and accumulates in pathogenic aggregates, much like other proteins linked to neurodegenerative diseases. However, the relative condensate and aggregate formation of the three brain-expressed ubiquilins is unknown. Here we report that the three ubiquilins differ in aggregation propensity, revealed by in-vitro experiments, cellular models, and analysis of human brain tissue. UBQLN4 displays heightened aggregation propensity over the other ubiquilins and, like amyloids, UBQLN4 forms ThioflavinT-positive fibrils in vitro. Measuring fluorescence recovery after photobleaching (FRAP) of puncta in cells, we report that all three ubiquilins undergo liquid-liquid phase transition. UBQLN2 and 4 exhibit slower recovery than UBQLN1, suggesting the condensates formed by these brain-expressed ubiquilins have different compositions and undergo distinct internal rearrangements. We conclude that while all brain-expressed ubiquilins exhibit self-association behavior manifesting as condensates, they follow distinct courses of phase-separation and aggregation. We suggest that this variability among ubiquilins along the continuum from liquid-like to solid informs both the normal ubiquitin-linked functions of ubiquilins and their accumulation and potential contribution to toxicity in neurodegenerative diseases.
MeSH term(s)	Autophagy-Related Proteins/chemistry ; Autophagy-Related Proteins/metabolism ; Brain/metabolism ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Protein Aggregates
Chemical Substances	Autophagy-Related Proteins ; Protein Aggregates
Language	English
Publishing date	2021-01-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-78775-4
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Article ; Online: Signature changes in ubiquilin expression in the R6/2 mouse model of Huntington's disease.

Safren, Nathaniel / Chang, Lydia / Dziki, Kristina M / Monteiro, Mervyn J

Brain research

2014 Volume 1597, Page(s) 37–46

Abstract: Ubiquilin proteins have been implicated in the cause and the pathology of neurodegenerative diseases. In the R6/2 mouse model of Huntington's disease (HD), ubiquilin levels decline during disease progression. Restoration of their levels by transgenic ... ...

Abstract	Ubiquilin proteins have been implicated in the cause and the pathology of neurodegenerative diseases. In the R6/2 mouse model of Huntington's disease (HD), ubiquilin levels decline during disease progression. Restoration of their levels by transgenic expression of ubiquilin-1 extends survival. Here we provide a comprehensive assessment of the expression and localization of all four ubiquilin proteins in both normal and R6/2-affected mice brains, using antibodies specific for each protein. Ubiquilin-1, 2 and 4 proteins were detected throughout the brain, with increased expression seen in the hippocampus and cerebellum. Ubiquilin-3 expression was not detected. All three ubiquilins expressed in the brain were found in Htt inclusions. Their expression changed during development and disease. Ubiquilin-1 and ubiquilin-2 protein levels decreased from 6 to 18 weeks of mouse development, independent of disease. Ubiquilin-1 and ubiquilin-4 protein levels also changed during HD disease progression. Ubiquilin-4 proteins that are normally expressed in the brain were lost and instead replaced by a novel 115 kDa higher molecular weight immunoreactive band. Taken together, our results demonstrate that all ubiquilin proteins are involved in HD pathology and that distinct changes in the signature of ubiquilin-4 expression could be useful for monitoring end-stage of HD disease.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport/genetics ; Adaptor Proteins, Vesicular Transport/metabolism ; Animals ; Autophagy-Related Proteins ; Brain/growth & development ; Brain/metabolism ; Brain/pathology ; Cell Line, Tumor ; Disease Models, Animal ; Disease Progression ; Fluorescent Antibody Technique ; Gene Knockdown Techniques ; HeLa Cells ; Humans ; Huntington Disease/metabolism ; Huntington Disease/pathology ; Inclusion Bodies/metabolism ; Inclusion Bodies/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; RNA, Small Interfering
Chemical Substances	Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport ; Autophagy-Related Proteins ; RNA, Small Interfering ; UBQLN1 protein, mouse ; UBQLN2 protein, mouse
Language	English
Publishing date	2014-12-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2014.12.008
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Article ; Online: Ubiquilin-2 differentially regulates polyglutamine disease proteins.

Gerson, Julia E / Safren, Nathaniel / Fischer, Svetlana / Patel, Ronak / Crowley, Emily V / Welday, Jacqueline P / Windle, Alexandra K / Barmada, Sami / Paulson, Henry L / Sharkey, Lisa M

Human molecular genetics

2020 Volume 29, Issue 15, Page(s) 2596–2610

Abstract: Divergent protein context helps explain why polyglutamine expansion diseases differ clinically and pathologically. This heterogeneity may also extend to how polyglutamine disease proteins are handled by cellular pathways of proteostasis. Studies suggest, ...

Abstract	Divergent protein context helps explain why polyglutamine expansion diseases differ clinically and pathologically. This heterogeneity may also extend to how polyglutamine disease proteins are handled by cellular pathways of proteostasis. Studies suggest, for example, that the ubiquitin-proteasome shuttle protein Ubiquilin-2 (UBQLN2) selectively interacts with specific polyglutamine disease proteins. Here we employ cellular models, primary neurons and mouse models to investigate the potential differential regulation by UBQLN2 of two polyglutamine disease proteins, huntingtin (HTT) and ataxin-3 (ATXN3). In cells, overexpressed UBQLN2 selectively lowered levels of full-length pathogenic HTT but not of HTT exon 1 fragment or full-length ATXN3. Consistent with these results, UBQLN2 specifically reduced accumulation of aggregated mutant HTT but not mutant ATXN3 in mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), respectively. Normally a cytoplasmic protein, UBQLN2 translocated to the nuclei of neurons in HD mice but not in SCA3 mice. Remarkably, instead of reducing the accumulation of nuclear mutant ATXN3, UBQLN2 induced an accumulation of cytoplasmic ATXN3 aggregates in neurons of SCA3 mice. Together these results reveal a selective action of UBQLN2 toward polyglutamine disease proteins, indicating that polyglutamine expansion alone is insufficient to promote UBQLN2-mediated clearance of this class of disease proteins. Additional factors, including nuclear translocation of UBQLN2, may facilitate its action to clear intranuclear, aggregated disease proteins like HTT.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Animals ; Ataxin-3/genetics ; Autophagy-Related Proteins/genetics ; Disease Models, Animal ; Exons ; Genetic Heterogeneity ; Humans ; Huntingtin Protein/genetics ; Huntington Disease/genetics ; Machado-Joseph Disease/genetics ; Mice ; Neurons/metabolism ; Neurons/pathology ; Peptides/genetics ; Proteasome Endopeptidase Complex
Chemical Substances	Adaptor Proteins, Signal Transducing ; Autophagy-Related Proteins ; Htt protein, mouse ; Huntingtin Protein ; Peptides ; UBQLN2 protein, mouse ; polyglutamine (26700-71-0) ; Ataxin-3 (EC 3.4.19.12) ; Atxn3 protein, mouse (EC 3.4.19.12) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2020-07-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddaa152
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