Protein–protein interactions of huntingtin in the hippocampus

Proskura, A. L.; Vechkapova, S. O.; Zapara, T. A.; Ратушняк, А. С.

doi:10.1134/s002689331704015x

Cited by 6 publications

(5 citation statements)

References 62 publications

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“…In normal conditions, Htt in axonal terminals interacts with synaptic vesicle proteins maintaining neurotransmitter release (42). The expansion of polyglutamine tract of Htt, however, influences its binding affinity, resulting in neuropathological changes (14).…”

Section: Discussionmentioning

confidence: 99%

Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington’s disease

Paraskevopoulou

Parvizi

Senger

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Transcriptional dysregulation in Huntington’s disease (HD) causes functional deficits in striatal neurons. Here, we performed Patch-sequencing (Patch-seq) in an in vitro HD model to investigate the effects of mutant Huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant Htt decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes whose dysregulation was correlated with physiological deficiencies in mutant Htt neurons. In support of a pivotal role for epigenetic mechanisms in HD pathophysiology, we found that inhibiting histone deacetylase 1/3 activities rectified several functional and morphological deficits and alleviated the aberrant transcriptional profiles in mutant Htt neurons. With this study, we demonstrate that Patch-seq technology can be applied both to better understand molecular mechanisms underlying a complex neurological disease at the single-cell level and to provide a platform for screening for therapeutics for the disease.

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Section: Discussionmentioning

confidence: 99%

Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington’s disease

Paraskevopoulou

Parvizi

Senger

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…At the moment, this problem has no solution, because the cellular functions of the wild-type of HTT remain poorly understood. Nevertheless, the results of HD studies allow us to outline the range of intracellular processes in which HTT is involved: firstly, vesicular [ 95 , 96 ] and organelle transport [ 97 ], endocytosis [ 98 ]; secondly, the process of autophagosome formation, degradation of proteins and whole organelles [ 99 , 100 , 101 ]; thirdly, mitosis [ 102 , 103 ]; and lastly, primary cilia formation process [ 43 , 104 ]. It looks like most of the cellular processes in which HTT is involved are associated with MTs and actin and/or mediated by them [ 42 ].…”

Section: Huntington’s Disease—a History Of Studies and Unanswered mentioning

confidence: 99%

Huntington’s Disease—An Outlook on the Interplay of the HTT Protein, Microtubules and Actin Cytoskeletal Components

Taran

Shuvalova

Lagarkova

et al. 2020

Cells

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Huntington’s disease is a severe and currently incurable neurodegenerative disease. An autosomal dominant mutation in the Huntingtin gene (HTT) causes an increase in the polyglutamine fragment length at the protein N-terminus. The consequence of the mutation is the death of neurons, mostly striatal neurons, leading to the occurrence of a complex of motor, cognitive and emotional-volitional personality sphere disorders in carriers. Despite intensive studies, the functions of both mutant and wild-type huntingtin remain poorly understood. Surprisingly, there is the selective effect of the mutant form of HTT even on nervous tissue, whereas the protein is expressed ubiquitously. Huntingtin plays a role in cell physiology and affects cell transport, endocytosis, protein degradation and other cellular and molecular processes. Our experimental data mining let us conclude that a significant part of the Huntingtin-involved cellular processes is mediated by microtubules and other cytoskeletal cell structures. The review attempts to look at unresolved issues in the study of the huntingtin and its mutant form, including their functions affecting microtubules and other components of the cell cytoskeleton.

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“…Conformational flexibility of PR65/A also helps regulate functions of its interacting proteins, such as enzyme activity, which is exemplified by the fact that PR65/A can act as elastic connector linking force and catalysis (Kaynak et al, 2023; Grinthal et al, 2010). Similar to PR65/A, HTT is a complex scaffold protein with multiple interaction partners and can also participate in modulating activity of its clients (Wanker et al, 2019; Proskura et al, 2017). Understanding the mechanisms of subtle modulations of HTT on protein–protein interactions and related cellular networks, as well as their alteration in HD, is essential for explaining the labyrinthine pathology of HD (Wanker et al, 2019; Proskura et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Similar to PR65/A, HTT is a complex scaffold protein with multiple interaction partners and can also participate in modulating activity of its clients (Wanker et al, 2019; Proskura et al, 2017). Understanding the mechanisms of subtle modulations of HTT on protein–protein interactions and related cellular networks, as well as their alteration in HD, is essential for explaining the labyrinthine pathology of HD (Wanker et al, 2019; Proskura et al, 2017). The results from this study will provide valuable information for further study.…”

Section: Discussionmentioning

confidence: 99%

Interaction between huntingtin exon 1 and HEAT repeat structure probed by chimeric model proteins

Zhang,

Wu,

Itzhaki

et al. 2023

Protein Science

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Huntington disease (HD) is associated with aggregation of Huntingtin (HTT) protein containing over 35 continuous Q residues within the N‐terminal exon 1 encoded region. The C‐terminal of the HTT protein consists mainly of HEAT repeat structure which serves as a scaffold for multiple cellular activities. Structural and biochemical analysis of the intact HTT protein has been hampered by its huge size (~300 kD) and most in vitro studies to date have focused on the properties of the exon 1 region. To explore the interaction between HTT exon 1 and the HEAT repeat structure, we constructed chimeric proteins containing the N‐terminal HTT exon 1 region and the HEAT repeat protein PR65/A. The results indicate that HTT exon 1 slightly destabilizes the downstream HEAT repeat structure and endows the HEAT repeat structure with more conformational flexibility. Wild‐type and pathological lengths of polyQ did not show differences in the interaction between HTT exon 1 and the HEAT repeats. With the C‐terminal fusion of PR65/A, HTT exon 1 containing pathological lengths of polyQ could still form amyloid fibrils, but the higher‐order architecture of fibrils and kinetics of fibril formation were affected by the C‐terminal fusion of HEAT repeats. This indicates that interaction between HTT exon 1 and HEAT repeat structure is compatible with both normal function of HTT protein and the pathogenesis of HD, and this study provides a potential model for further exploration.This article is protected by copyright. All rights reserved.

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Protein–protein interactions of huntingtin in the hippocampus

Cited by 6 publications

References 62 publications

Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington’s disease

Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington’s disease

Huntington’s Disease—An Outlook on the Interplay of the HTT Protein, Microtubules and Actin Cytoskeletal Components

Interaction between huntingtin exon 1 and HEAT repeat structure probed by chimeric model proteins

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