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Maniv I, Sarji M, Bdarneh A, Feldman A, Ankawa R, Koren E, Magid-Gold I, Reis N, Soteriou D, Salomon-Zimri S, Lavy T, Kesselman E, Koifman N, Kurz T, Kleifeld O, Michaelson D, van Leeuwen FW, Verheijen BM, Fuchs Y, Glickman MH. Altered ubiquitin signaling induces Alzheimer's disease-like hallmarks in a three-dimensional human neural cell culture model. Nat Commun. 2023 Sep 22;14(1):5922. PubMed.
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Karolinska Institutet
This is a very interesting paper. It is good to see that the authors brought testing of the UBB+1 hypothesis to the next level. It was also good to see that Fred van Leeuwen, who discovered molecular misreading and UBB+1, was involved in this study before his passing (the paper is dedicated to him).
The observations in that UBB+1 is already present in early stages of Alzheimer’s, and that in various genetic models for Alzheimer’s disease UBB+1 accumulates, strengthen the idea that accumulation of UBB+1 is a common feature in Alzheimer’s. Combined with earlier studies that showed UBB+1 is a substrate of the ubiquitin-proteasome system (UPS), and that under physiological conditions it is efficiently cleared by the UPS, this work suggests that defects in this proteolytic system may occur in Alzheimer’s independent of the underlying genetic cause, and that these defects may be apparent early in the pathology.
It has been known for a long time that accumulated UBB+1 is not only cleared by the UPS, but also can impair the functionality of this system. In the current study it is proposed that its interaction with UCH-L1 plays an important role, but I would consider it likely that interference with other ubiquitin-interacting proteins may also contribute to its negative effect in the UPS.
That accumulation of UBB+1 is a common phenomenon in Alzheimer’s, occurs early in the cellular pathology, and seems to contribute to cellular dysfunction, makes it interesting from a therapeutic point of view. It implies that preventing accumulation of UBB+1 may have a beneficial effect in Alzheimer’s. This is supported by what is, in my opinion, the most exciting part in the study, namely that the authors were able to show that selective depletion of endogenously produced UBB+1 reduces pathology in a cellular model. That is a major achievement.
Therapeutic targeting of UBB+1 may be hard because it lacks catalytic activity, and therefore efforts should be aimed at reducing levels of UBB+1. An important issue to address is the role of UBB+1 in Alzheimer’s etiology in an animal model, as it has been shown previously that in mice UBB+1 overexpression reduced the load of Aβ, which seems to contrast the current finding (Verheijen et al., 2018). Unfortunately, the authors did not cite or comment on this earlier study, which seems highly relevant for the current finding. While I don’t think that the data necessarily conflict, they may be confusing at first sight, deserve some discussion.
I think one of the most urgent issues is to understand why UBB+1 accumulates in Alzheimer’s disease. By understanding the reasons for its accumulation, which likely relate to problems in protein quality control and clearance, it may be possible to identify key players that will be more amenable to therapeutic targeting.
References:
Verheijen BM, Stevens JA, Gentier RJ, van 't Hekke CD, van den Hove DL, Hermes DJ, Steinbusch HW, Ruijter JM, Grimm MO, Haupenthal VJ, Annaert W, Hartmann T, van Leeuwen FW. Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model. Neurobiol Aging. 2018 Dec;72:62-71. Epub 2018 Aug 18 PubMed.
View all comments by Nico DantumaThe University of Minnesota
I think it is quite intriguing that UBB+1 specifically targets AD pathologies (Aβ and p-tau), but not other pathologies, such as α-synuclein. It would be important to know how UBB+1 selectively modulates APP degradation, but not the degradation of other proteins, through proteasome pathways.
The authors tested UBB+1 in 3-D iPSC cell models expressing human FAD mutations. I wonder if similar phenotypes can be seen in cell models expressing sporadic AD risk variants, such as ApoE4. I think it would be critical to know if the interaction between UBB+1 and UCHL is detectable in human AD brains during disease development and progression, and whether this interaction is key to the development of Ab and tau aggregates, before we consider UBB+1 as a therapeutic target.
View all comments by Dongming CaiColumbia University
This research by Maniv et al. provides further insights into the molecular connection between UBB+1 and the pathology of Alzheimer's disease (AD). UBB+1, a ubiquitin RNA frameshift mutation identified by van Leeuwen and colleagues more than two decades ago, has been the subject of numerous studies investigating its role in AD and other neurodegenerative conditions (van Leeuwen et al., 1998).
This study presents an intriguing perspective by exploring whether the initial sequence of events involving proteolysis (specifically, defective ubiquitination) may be a contributing cause, rather than a consequence, of AD. Addressing this question poses a considerable challenge, as dysregulated proteostasis is typically regarded as a downstream event in the early pathogenesis of AD.
The findings convincingly demonstrate that viral overexpression of UBB+1 in 3D human cell cultures leads to the formation of pathological markers associated with AD. However, there remains some uncertainty regarding the reasons for the accumulation of UBB+1 in the early Braak stages of AD. Further investigation is needed to determine if mouse models exhibiting amyloid plaques and tau aggregation can faithfully replicate observations from human studies. Additionally, it is important to ascertain whether non-neuronal cells within the brain also accumulate UBB+1.
In terms of mechanistic insights, the study elegantly proposes that UBB+1 competes with ubiquitin for binding to UCHL1, thereby hindering its role in facilitating the proteolysis of amyloid precursor protein (APP). However, questions persist regarding whether proteasome and autophagy activities are directly or indirectly impacted by UBB+1. Notably, the study did not detect an increase in polyubiquitin chains in three-dimensional cultures overexpressing UBB+1, despite known occurrences of ubiquitin inclusions and decreased proteolysis in AD and in AD models.
This research presents a promising novel target for AD and underscores the multiple levels within the ubiquitin-proteasome system that can be potentially targeted, including ubiquitination, ligases, deubiquitinating enzymes, and proteasome complex levels.
References:
van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, Sluijs JA, Köycü S, Ramdjielal RD, Salehi A, Martens GJ, Grosveld FG, Peter J, Burbach H, Hol EM. Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science. 1998 Jan 9;279(5348):242-7. PubMed.
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