HAP40 protein levels are huntingtin-dependent and decrease in Huntington disease

Huang, Bin; Seefelder, Manuel; Buck, Eva; Engler, Tatjana; Lindenberg, Katrin S.; Klein, Fabrice; Landwehrmeyer, G. Bernhard; Kochanek, Stefan

doi:10.1016/j.nbd.2021.105476

Cited by 12 publications

(27 citation statements)

References 43 publications

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“…As an essential regulator of HTT, some key questions are how HAP40 affects the toxicity of mutant HTT, and whether the HAP40-free mutant HTT is more or less toxic. Contrary to an early report [ 35 ], we found that HAP40 levels were not elevated in HD cells ( Fig 9 ), a result that was also observed in two recent reports [ 57 , 58 ]. Such a result would be a natural extension from our findings that polyQ expansion in HTT did not affect its binding with HAP40 (Figs 8 and S8 ) and their mutual dependence on protein stability ( Fig 5 ), and that the majority, if not all, of HAP40 protein should be in complex with HTT, as most HTT-free HAP40 is quickly cleared away by the proteasome (Figs 5 – 7 ).…”

Section: Discussioncontrasting

confidence: 81%

HAP40 is a conserved central regulator of Huntingtin and a potential modulator of Huntington’s disease pathogenesis

et al. 2022

PLoS Genet

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Perturbation of huntingtin (HTT)’s physiological function is one postulated pathogenic factor in Huntington’s disease (HD). However, little is known how HTT is regulated in vivo. In a proteomic study, we isolated a novel ~40kDa protein as a strong binding partner of Drosophila HTT and demonstrated it was the functional ortholog of HAP40, an HTT associated protein shown recently to modulate HTT’s conformation but with unclear physiological and pathologic roles. We showed that in both flies and human cells, HAP40 maintained conserved physical and functional interactions with HTT. Additionally, loss of HAP40 resulted in similar phenotypes as HTT knockout. More strikingly, HAP40 strongly affected HTT’s stability, as depletion of HAP40 significantly reduced the levels of endogenous HTT protein while HAP40 overexpression markedly extended its half-life. Conversely, in the absence of HTT, the majority of HAP40 protein were degraded, likely through the proteasome. Further, the affinity between HTT and HAP40 was not significantly affected by polyglutamine expansion in HTT, and contrary to an early report, there were no abnormal accumulations of endogenous HAP40 protein in HD cells from mouse HD models or human patients. Lastly, when tested in Drosophila models of HD, HAP40 partially modulated the neurodegeneration induced by full-length mutant HTT while showed no apparent effect on the toxicity of mutant HTT exon 1 fragment. Together, our study uncovers a conserved mechanism governing the stability and in vivo functions of HTT and demonstrates that HAP40 is a central and positive regulator of endogenous HTT. Further, our results support that mutant HTT is toxic regardless of the presence of its partner HAP40, and implicate HAP40 as a potential modulator of HD pathogenesis through its multiplex effect on HTT’s function, stability and the potency of mutant HTT’s toxicity.

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Section: Discussioncontrasting

confidence: 81%

HAP40 is a conserved central regulator of Huntingtin and a potential modulator of Huntington’s disease pathogenesis

et al. 2022

PLoS Genet

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“…However, taken together, the observations summarized in the previous section show that the co-evolution of HTT and HAP40 has selected an exceptionally stable complex, suggesting that this stability may be needed for HTT-HAP40 function. This aligns with the findings that HAP40 is degraded rapidly when HTT is knocked down, whereas it is stabilized in the presence of HTT [24,47].…”

Section: In Vivo Stabilitysupporting

confidence: 91%

“…In a first study comparing Q23-, Q46-, and Q78-apo-HTT proteins, a large majority of intra-HTT cross-links were common to all three or at least two proteins, Another caveat, suggested by our understanding of apo-HTT behavior in vitro, concerns the use of over-expressed HTT to identify potential physiological partners. We showed that, upon HTT over-expression, the HAP40 protein level also increases, suggesting that part of the over-expressed HTT is "buffered" in a complex with HAP40 [47]. This means, on the one hand, that partners copurifying with HTT may in fact be interactors of the HTT-HAP40 complex.…”

Section: In Vivo Stabilitymentioning

confidence: 88%

“…Is it even possible that such a large protein, whose domains are exposing large hydrophobic surfaces, remains unbound? Since HTT and HAP40 share large hydrophobic interphases [22], we speculated that a specific function of HAP40 could be to shield hydrophobic patches of HTT, thereby preventing aggregation [47]. The stable HTT-HAP40 complex…”

Section: In Vivo Stabilitymentioning

confidence: 99%

“…The exceptional stability [24] and in vivo abundance of the HTT-HAP40 complex [31,39,47,55], the common origin of these proteins at the root of eukaryotes, and their likely coevolution [40] suggest functional relevance of the complex (Fig. 3).…”

Section: U N C O R R E C T E D a U T H O R P R O O Fmentioning

confidence: 99%

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Huntingtin and Its Partner Huntingtin-Associated Protein 40: Structural and Functional Considerations in Health and Disease

Seefelder

Klein

Landwehrmeyer

et al. 2022

JHD

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Since the discovery of the mutation causing Huntington’s disease (HD) in 1993, it has been debated whether an expanded polyglutamine (polyQ) stretch affects the properties of the huntingtin (HTT) protein and thus contributes to the pathological mechanisms responsible for HD. Here we review the current knowledge about the structure of HTT, alone (apo-HTT) or in a complex with Huntingtin-Associated Protein 40 (HAP40), the influence of polyQ-length variation on apo-HTT and the HTT-HAP40 complex, and the biology of HAP40. Phylogenetic analyses suggest that HAP40 performs essential functions. Highlighting the relevance of its interaction with HTT, HAP40 is one of the most abundant partners copurifying with HTT and is rapidly degraded, when HTT levels are reduced. As the levels of both proteins decrease during disease progression, HAP40 could also be a biomarker for HD. Whether declining HAP40 levels contribute to disease etiology is an open question. Structural studies have shown that the conformation of apo-HTT is less constrained but resembles that adopted in the HTT-HAP40 complex, which is exceptionally stable because of extensive interactions between HAP40 and the three domains of HTT. The complex— and to some extent apo-HTT— resists fragmentation after limited proteolysis. Unresolved regions of apo-HTT, constituting about 25% of the protein, are the main sites of post-translational modifications and likely have major regulatory functions. PolyQ elongation does not substantially alter the structure of HTT, alone or when associated with HAP40. Particularly, polyQ above the disease length threshold does not induce drastic conformational changes in full-length HTT. Therefore, models of HD pathogenesis stating that polyQ expansion drastically alters HTT properties should be reconsidered.

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The amyloid state of proteins: A boon or bane?

Hassan

Nabi

Khan

et al. 2022

International Journal of Biological Macromolecules

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HAP40 protein levels are huntingtin-dependent and decrease in Huntington disease

Cited by 12 publications

References 43 publications

HAP40 is a conserved central regulator of Huntingtin and a potential modulator of Huntington’s disease pathogenesis

HAP40 is a conserved central regulator of Huntingtin and a potential modulator of Huntington’s disease pathogenesis

Huntingtin and Its Partner Huntingtin-Associated Protein 40: Structural and Functional Considerations in Health and Disease

The amyloid state of proteins: A boon or bane?

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