Annemieke Aartsma-Rus
@oligogirl.bsky.social
Translating science from bench to bedside and from jargon to lay language
Very nice paper and I like the systematic approach authors did and also the validation studies to make sure the model was suitable AND using wild type littermates for the behavioral studies.
November 24, 2025 at 9:24 AM
Very nice paper and I like the systematic approach authors did and also the validation studies to make sure the model was suitable AND using wild type littermates for the behavioral studies.
While this study provides useful insights in the treatment window of Angelman syndrome, which thus facilitates more realistic expectations of a UBE3A restoring treatment, authors warn that the windows for other genes involved in neurodevelopmental disorders may vary.
November 24, 2025 at 9:23 AM
While this study provides useful insights in the treatment window of Angelman syndrome, which thus facilitates more realistic expectations of a UBE3A restoring treatment, authors warn that the windows for other genes involved in neurodevelopmental disorders may vary.
Furthermore, mice and human differ. While Ube3a expression also only arises from the maternal allele in mice, brain development between mice and humans vastly differ, as human brain takes very long to mature. Authors speculate that a 3 week mouse brain likely reflects a 2 year human brain.
November 24, 2025 at 9:22 AM
Furthermore, mice and human differ. While Ube3a expression also only arises from the maternal allele in mice, brain development between mice and humans vastly differ, as human brain takes very long to mature. Authors speculate that a 3 week mouse brain likely reflects a 2 year human brain.
Authors discuss that the critical treatment window for full motor deficit improvement appears to be between 3 and 6 weeks, while for the behavioral and anxiety symptoms it is before birth. Authors discuss the limitation of their studies: they were done in an inbred mouse strain.
November 24, 2025 at 9:21 AM
Authors discuss that the critical treatment window for full motor deficit improvement appears to be between 3 and 6 weeks, while for the behavioral and anxiety symptoms it is before birth. Authors discuss the limitation of their studies: they were done in an inbred mouse strain.
Authors finally started treatment in neonates, via the milk of the dams. This resulted in 50% Ube3a expression (less efficient that direct tamoxifen treatment). Here the motor deficits were improved, but the behavioral ones were not, confirming that the treatment window there is during embryogenesis
November 24, 2025 at 9:18 AM
Authors finally started treatment in neonates, via the milk of the dams. This resulted in 50% Ube3a expression (less efficient that direct tamoxifen treatment). Here the motor deficits were improved, but the behavioral ones were not, confirming that the treatment window there is during embryogenesis
Thus that symptom is treatable by targeting downstream pathways, but restoring Ube3a expression is not therapeutic. The electrophysiological deficits in the hippocampus however were all normalized after reactivation of Ube3a expression, even in the adults.
November 24, 2025 at 9:17 AM
Thus that symptom is treatable by targeting downstream pathways, but restoring Ube3a expression is not therapeutic. The electrophysiological deficits in the hippocampus however were all normalized after reactivation of Ube3a expression, even in the adults.
No improvement was seen when Ube3a expression was activated in adult mice. For anxiety and behavioral deficits, there was no treatment effect for any of the timepoints of Ube3a expression activation. However, authors show that anti-epileptic drugs were able to prevent seizures.
November 24, 2025 at 9:15 AM
No improvement was seen when Ube3a expression was activated in adult mice. For anxiety and behavioral deficits, there was no treatment effect for any of the timepoints of Ube3a expression activation. However, authors show that anti-epileptic drugs were able to prevent seizures.
So the model was validated. Then authors activated the Ube3a expression at 3, 6 and 14 weeks of age in the mice (juvenile, adolescent and adult). Protein levels were 70-100%. Juvenile activation resulted in full normalization of motor deficits, while adolescent activation partially restored this.
November 24, 2025 at 9:11 AM
So the model was validated. Then authors activated the Ube3a expression at 3, 6 and 14 weeks of age in the mice (juvenile, adolescent and adult). Protein levels were 70-100%. Juvenile activation resulted in full normalization of motor deficits, while adolescent activation partially restored this.
Authors confirmed lack of Ube3a expression. These conditional mice without tamoxifen treatment presented as Ube3a knockouts. Upon tamoxifen treatment Ube3a expression was 80-99% in various brain regions and these mice behaved as wild types.
November 24, 2025 at 9:09 AM
Authors confirmed lack of Ube3a expression. These conditional mice without tamoxifen treatment presented as Ube3a knockouts. Upon tamoxifen treatment Ube3a expression was 80-99% in various brain regions and these mice behaved as wild types.
Likely there is a critical time window for different aspects of the pathology. Authors here did a systematic study in a conditional Ube3a mouse model, where Ube3a expression is blocked but can be reinitiated after tamoxifen induced CRE-recombination.
November 24, 2025 at 9:07 AM
Likely there is a critical time window for different aspects of the pathology. Authors here did a systematic study in a conditional Ube3a mouse model, where Ube3a expression is blocked but can be reinitiated after tamoxifen induced CRE-recombination.
The silencing happens via a long non-coding RNA, UBE3A-AST. Silencing or degrading this transcript is a therapeutic approach to restore UBE3A expression (from the paternal allele). The question is however, to what extent this will be therapeutic, as part of the deficits arise during embryogenesis.
November 24, 2025 at 9:06 AM
The silencing happens via a long non-coding RNA, UBE3A-AST. Silencing or degrading this transcript is a therapeutic approach to restore UBE3A expression (from the paternal allele). The question is however, to what extent this will be therapeutic, as part of the deficits arise during embryogenesis.
Angelman syndrome is a neurodevelopmental disease characterized by developmental delay, motor impairments, intellectual disability, epileptic seizures and lack of speech. It is caused by mutations in the maternally inherited UBE3A gene. The paternal copy is functional but silenced in neurons.
November 24, 2025 at 9:04 AM
Angelman syndrome is a neurodevelopmental disease characterized by developmental delay, motor impairments, intellectual disability, epileptic seizures and lack of speech. It is caused by mutations in the maternally inherited UBE3A gene. The paternal copy is functional but silenced in neurons.
Furthermore, they propose that an inducible dystrophin expression mice would be useful to elucidate pathways further. So as always more work is needed, but this work confirms that earlier treatment in Duchenne patients is important (though in utero treatment would be very challenging)
November 21, 2025 at 9:34 AM
Furthermore, they propose that an inducible dystrophin expression mice would be useful to elucidate pathways further. So as always more work is needed, but this work confirms that earlier treatment in Duchenne patients is important (though in utero treatment would be very challenging)
Authors discuss that more work is needed to study e.g. also the role of fibroadipogenic stem cells in embryonic development. It is known that the cells play a role in postnatal muscle pathology in Duchenne, but they might already play a role earlier in utero as well.
November 21, 2025 at 9:32 AM
Authors discuss that more work is needed to study e.g. also the role of fibroadipogenic stem cells in embryonic development. It is known that the cells play a role in postnatal muscle pathology in Duchenne, but they might already play a role earlier in utero as well.
To confirm this authors artificially increase Mark2 levels in mdx mice via a different route (using mice that do not have Akt protein, meaning Numb is activated to increase Mark2). This indeed improved the secondary proliferation in mdx mice and resulted in larger muscle fibers.
November 21, 2025 at 9:31 AM
To confirm this authors artificially increase Mark2 levels in mdx mice via a different route (using mice that do not have Akt protein, meaning Numb is activated to increase Mark2). This indeed improved the secondary proliferation in mdx mice and resulted in larger muscle fibers.
MARK2 is a protein involved in maintaining polarity. Dystrophin was expressed in wild type muscle, but reduced after proliferation. However, it was expressed in quiescent cells. Lacking dystrophin, mdx muscle had reduced levels of Mark2, which could be the cause of reduced secondary myogenesis.
November 21, 2025 at 9:29 AM
MARK2 is a protein involved in maintaining polarity. Dystrophin was expressed in wild type muscle, but reduced after proliferation. However, it was expressed in quiescent cells. Lacking dystrophin, mdx muscle had reduced levels of Mark2, which could be the cause of reduced secondary myogenesis.
Also the muscle fibers are smaller and there are less Pax7 and MyoG expressing cells (marker for satellite cells). Note that the differences are not that big, but there is a clear reduction. Authors performed single cell sequencing showing again reduced levels of committed muscle stem cells in mdx.
November 21, 2025 at 9:27 AM
Also the muscle fibers are smaller and there are less Pax7 and MyoG expressing cells (marker for satellite cells). Note that the differences are not that big, but there is a clear reduction. Authors performed single cell sequencing showing again reduced levels of committed muscle stem cells in mdx.
In the paper, authors analysis show that in mdx mice the development of primary myogenesis is slightly slower, but the numbers of primary myocytes are the same. However, during secondary myogenesis authors showed that in mdx mice there are less proliferating and less committed muscle stem cells
November 21, 2025 at 9:25 AM
In the paper, authors analysis show that in mdx mice the development of primary myogenesis is slightly slower, but the numbers of primary myocytes are the same. However, during secondary myogenesis authors showed that in mdx mice there are less proliferating and less committed muscle stem cells
Myogenesis (muscle formation) happens in 2 stages. First early in development primary muscle fibersare formed in small amounts. Then later on, in a second, larger wave of proliferation, more mature muscles are formed.
November 21, 2025 at 9:24 AM
Myogenesis (muscle formation) happens in 2 stages. First early in development primary muscle fibersare formed in small amounts. Then later on, in a second, larger wave of proliferation, more mature muscles are formed.
Here they wanted to study the impact of less of dystrophin on muscle development in mouse embryos. For this they used wild type and mdx mice (no dystrophin) and a marker systems where early muscle progenitors are red and committed muscle stem cells are green.
November 21, 2025 at 9:18 AM
Here they wanted to study the impact of less of dystrophin on muscle development in mouse embryos. For this they used wild type and mdx mice (no dystrophin) and a marker systems where early muscle progenitors are red and committed muscle stem cells are green.
An important point authors make is that pathology does not start when patients are diagnosed (3-5 years usually) or when they start showing symptoms (delayed motor milestones and falls etc 18m-3 years), but that it starts already in utero (patients are born with high creatine kinase levels in blood)
November 21, 2025 at 9:17 AM
An important point authors make is that pathology does not start when patients are diagnosed (3-5 years usually) or when they start showing symptoms (delayed motor milestones and falls etc 18m-3 years), but that it starts already in utero (patients are born with high creatine kinase levels in blood)
This polarity is important to make sure one satellite cell goes back to its quiescent state for future regenerative needs. Authors argue that this could potentially also have an impact on embryonic muscle development. This fits with the fact that patients are born with muscle pathology.
November 21, 2025 at 9:15 AM
This polarity is important to make sure one satellite cell goes back to its quiescent state for future regenerative needs. Authors argue that this could potentially also have an impact on embryonic muscle development. This fits with the fact that patients are born with muscle pathology.
Duchenne muscular dystrophy is caused by lack of dystrophin. This results in muscle fiber damage. However, authors previously have shown that dystrophin protein also plays a role in muscle stem cell division, especially in maintaining cell polarity
November 21, 2025 at 9:14 AM
Duchenne muscular dystrophy is caused by lack of dystrophin. This results in muscle fiber damage. However, authors previously have shown that dystrophin protein also plays a role in muscle stem cell division, especially in maintaining cell polarity