The Dose-Dependent Pleiotropic Effects of the UBB+1 Ubiquitin Mutant

Banasiak, Katarzyna; Szulc, Natalia A; Pokrzywa, Wojciech

doi:10.3389/fmolb.2021.650730

Front. Mol. Biosci.

2021

DOI: 10.3389/fmolb.2021.650730

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The Dose-Dependent Pleiotropic Effects of the UBB+1 Ubiquitin Mutant

Katarzyna Banasiak

Natalia A Szulc²,

Wojciech Pokrzywa³

Abstract: The proteolytic machinery activity diminishes with age, leading to abnormal accumulation of aberrant proteins; furthermore, a decline in protein degradation capacity is associated with multiple age-related proteinopathies. Cellular proteostasis can be maintained via the removal of ubiquitin (Ub)-tagged damaged and redundant proteins by the ubiquitin-proteasome system (UPS). However, during aging, central nervous system (CNS) cells begin to express a frameshift-mutated Ub, UBB+1. Its accumulation is a neuropath… Show more

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Cited by 4 publications

References 82 publications

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Innovative pathological network‐based multitarget approaches for Alzheimer's disease treatment

Mayo,

Pascual,

Crisman

et al. 2024

Medicinal Research Reviews

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Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is a major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance. Intensive AD research describes this disease as a highly complex multifactorial disease. Disclosure of novel pathological pathways and their interconnections has had a major impact on medicinal chemistry drug development for AD over the last two decades. The complex network of pathological events involved in the onset of the disease has prompted the development of multitarget drugs. These chemical entities combine pharmacological activities toward two or more drug targets of interest. These multitarget‐directed ligands are proposed to modify different nodes in the pathological network aiming to delay or even stop disease progression. Here, we review the multitarget drug development strategy for AD during the last decade.

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Innovative pathological network‐based multitarget approaches for Alzheimer's disease treatment

Mayo,

Pascual,

Crisman

et al. 2024

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

Neural EGFL-like 1, a craniosynostosis-related osteochondrogenic molecule, strikingly associates with neurodevelopmental pathologies

Li,

Zheng,

et al. 2023

Cell Biosci

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Various craniofacial syndromes cause skeletal malformations and are accompanied by neurological abnormalities at different levels, leading to tremendous biomedical, financial, social, and psychological burdens. Accumulating evidence highlights the importance of identifying and characterizing the genetic basis that synchronously modulates musculoskeletal and neurobehavioral development and function. Particularly, previous studies from different groups have suggested that neural EGFL-like-1 (Nell-1), a well-established osteochondrogenic inducer whose biopotency was initially identified in the craniofacial tissues, may also play a vital role in the central nervous system, particularly regarding neurological disorder pathologies. To provide first-hand behavior evidence if Nell-1 also has a role in central nervous system abnormalities, we compared the Nell-1-haploinsufficient (Nell-1+/6R) mice with their wild-type counterparts regarding their repetitive, social communication, anxiety-related, locomotor, sensory processing-related, motor coordination, and Pavlovian learning and memory behaviors, as well as their hippocampus transcriptional profile. Interestingly, Nell-1+/6R mice demonstrated core autism spectrum disorder-like deficits, which could be corrected by Risperidone, an FDA-approved anti-autism, anti-bipolar medicine. Besides, transcriptomic analyses identified 269 differential expressed genes, as well as significantly shifted alternative splicing of ubiquitin B pseudogene Gm1821, in the Nell-1+/6R mouse hippocampus, which confirmed that Nell-1 plays a role in neurodevelopment. Therefore, the current study verifies that Nell-1 regulates neurological development and function for the first time. Moreover, this study opens new avenues for understanding and treating craniofacial patients suffering from skeletal deformities and behavior, memory, and cognition difficulties by uncovering a novel bone-brain-crosstalk network. Furthermore, the transcriptomic analysis provides the first insight into deciphering the mechanism of Nell-1 in neurodevelopment.

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Excess Ub-K48 Induces Neuronal Apoptosis in Alzheimer’s Disease

Li,

Yuan,

Huang

et al. 2024

J. Integr. Neurosci.

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Background: K48-linked ubiquitin chain (Ub-K48) is a crucial ubiquitin chain implicated in protein degradation within the ubiquitin-proteasome system. However, the precise function and molecular mechanism underlying the role of Ub-K48 in the pathogenesis of Alzheimer’s disease (AD) and neuronal cell abnormalities remain unclear. The objective of this study was to examine the function of K48 ubiquitination in the etiology of AD, and its associated mechanism of neuronal apoptosis. Methods: A mouse model of AD was constructed, and behavioral phenotypic changes were detected using an open field test (OFT). The expression of glial fibrillary acidic protein (GFAP), an early marker of AD, was detected by western blotting (WB). Neuronal apoptosis in the hippocampal region was assessed by hematoxylin and eosin (HE) and Nissl staining. Immunohistochemistry and immunofluorescence were performed to observe the changes in Phosphorylated tubulin associated unit (p-Tau) and Ub-K48 colocalization in neurons of the hippocampal region of AD mice. WB was further applied to detect the degree of ubiquitylation of K48 and the expression of Tau, p-Tau, B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X (Bax) proteins in neuronal cells of the hippocampus and cortical regions of mice. Results: Mice with AD exhibited significantly longer resting times (p < 0.05) and shorter average speeds (p < 0.01), total distances travelled (p < 0.01), and distances travelled (p < 0.01) in the central region than those in the control group. This indicated cognitive impairment, which occurred concurrent with an increased expression of the AD marker GFAP protein (p < 0.001). The hippocampal region of AD mice showed abnormalities with sparsely and irregularly arranged cells, large gaps between cells, lighter staining, unclear boundaries of the cell membranes and nuclei, and agglutinated and condensed nuclei (p < 0.01). The neuronal cells of AD mice exhibited significantly elevated levels of p-Tau (p < 0.01) and Ub-K48 (p < 0.01), as well as a notable degree of co-localization within the cells. The intracellular pro-inflammatory protein Bax was significantly upregulated (p < 0.05), while the Bcl-2/Bax ratio was significantly lower than that in the control group (p < 0.05), thus inducing apoptosis in AD neuronal cells. Conclusion: Ub-K48 is strongly linked to the development of AD. p-Tau aggregate in neuronal cells in the hippocampal region of the AD brain and colocalize with Ub-K48, which in turn leads to cellular inflammation and the induction of apoptosis in neuronal cells.

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The Dose-Dependent Pleiotropic Effects of the UBB+1 Ubiquitin Mutant

Cited by 4 publications

References 82 publications

Innovative pathological network‐based multitarget approaches for Alzheimer's disease treatment

Innovative pathological network‐based multitarget approaches for Alzheimer's disease treatment

Neural EGFL-like 1, a craniosynostosis-related osteochondrogenic molecule, strikingly associates with neurodevelopmental pathologies

Excess Ub-K48 Induces Neuronal Apoptosis in Alzheimer’s Disease

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