Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease

Li, Mei; Yasumura, Douglas; K., Aye Aye; Matthes, Michael T.; Yang, Hongbo; Nielson, Gregory N.; Huang, Yong; Szoka, Francis C.; LaVail, Matthew M.; Diamond, Marc I.

doi:10.1371/journal.pone.0056026

Cited by 43 publications

(43 citation statements)

References 37 publications

(68 reference statements)

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“…However, The HD group has been analysed as a whole, and also separated into Manifest HD and pre-manifest HD groups. p values have been given for comparisons between the complete HD group and control participants * Denotes significance J Neurol drosophila and mouse models of HD, present with severe neuropathology, including progressive disorganisation of the photoreceptor layer and retinal dysfunction suggesting that the retina may exhibit the same neuronal pathology as the rest of the brain [39,[42][43][44][45]. In our study, inspection of OCT images did not reveal any obvious photoreceptor abnormalities.…”

Section: Discussionmentioning

confidence: 47%

Optical coherence tomography findings in Huntington’s disease: a potential biomarker of disease progression

et al. 2015

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Previous reports of ocular abnormalities in Huntington's disease (HD) have detailed eye movement disorders. The objective of this case-control study was to investigate optic nerve and macular morphology in HD using optical coherence tomography (OCT). A total of 26 HD patients and 29 controls underwent a thorough ophthalmic examination including spectral domain OCT scans of the macula and peripapillary retinal nerve fibre layer (RNFL). Genetic testing results, disease duration, HD disease burden scores and Unified HD Rating Scale motor scores were acquired for HD patients. Temporal RNFL thickness was significantly reduced in the HD group (62.3 vs. 69.8 μm, p = 0.005), and there was a significant negative correlation between temporal RNFL thickness and disease duration (R (2) = -0.51, p = 0.04). Average peripapillary RNFL thickness was not significantly different between the HD and control groups. There was a significant negative correlation between macular volume and disease duration (R (2) = -0.71, p = 0.002), and motor scores (R (2) = -0.56, p = 0.01). Colour vision was significantly poorer in the HD group. Temporal RNFL is preferentially thinned in HD patients, possibly implicating mitochondrial dysfunction as the temporal RNFL is reduced in the patients with some mitochondrial disorders, including Leber's hereditary optic neuropathy. The correlation between the decrease in macular volume and temporal RNFL, and increasing disease severity suggests that OCT may be a useful biomarker for disease progression in HD. Larger, longitudinal studies are required.

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Section: Discussionmentioning

confidence: 47%

Optical coherence tomography findings in Huntington’s disease: a potential biomarker of disease progression

et al. 2015

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“…From a phenotypic standpoint, gain-offunction toxicity resulting from the accumulation of S-and F-phase species appears to be weakened by interactions with profilin (91). It is also conceivable that other heterotypic interactions with Htt-NTFs modulate phase boundaries in very different ways.…”

Section: Understanding the Effects Of Htt-ntf Binding Partners In Termentioning

confidence: 99%

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Posey

Ruff

Harmon

et al. 2018

Journal of Biological Chemistry

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119

117

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Huntingtin N-terminal fragments (Htt-NTFs) with expanded polyglutamine tracts form a range of neurotoxic aggregates that are associated with Huntington's disease. Here, we show that aggregation of Htt-NTFs, irrespective of polyglutamine length, yields at least three phases (designated M, S, and F) that are delineated by sharp concentration thresholds and distinct aggregate sizes and morphologies. We find that monomers and oligomers make up the soluble M-phase, ~25 nm spheres dominate in the soluble S-phase, and long, linear fibrils make up the insoluble F-phase. Previous studies showed that profilin, an abundant cellular protein, reduces Htt-NTF aggregation and toxicity in cells. We confirm that profilin achieves its cellular effects through direct binding to the C-terminal proline-rich region of Htt-NTFs. We show that profilin preferentially binds to Htt-NTF M-phase species and destabilizes aggregation and phase separation by shifting the concentration boundaries for phase separation to higher values through a process known as polyphasic linkage. Our experiments, aided by coarse-grained computer simulations and theoretical analysis, suggest that preferential binding of profilin to the Mphase species of Htt-NTFs is enhanced through a combination of specific interactions between profilin and polyproline segments and auxiliary interactions between profilin and polyglutamine tracts. Polyphasic linkage may be a general strategy that cells utilize to regulate phase behavior of aggregation-prone proteins. Accordingly, detailed knowledge of phase behavior and an understanding of how ligands modulate phase boundaries may pave the way for developing new therapeutics against a variety of aggregation-prone proteins.Many diseases are associated with protein misfolding and aggregation (1,2). The aggregation process is often characterized by the presence of one or more threshold concentrations at which a sharp, discontinuous change to some aspect of the assembly state (e.g., size, conformational characteristics, material properties) occurs (3-6). Such a change can be described using the concepts of phase transitions. Phase separation, a subcategory of phase transitions, has recently received considerable attention due to increasing recognition of its importance in cell biology (7)(8)(9)(10)(11)(12)(13). Phase separation refers to aggregation-related changes in molecular density that give rise to the coexistence of dilute macromolecule-deficient phases and dense macromolecule-rich phases (3,14,15). Examples of multiple coexisting phases have been observed in biological contexts (15)(16)(17)(18), and these phases can be liquid, solid, or semisolid (e.g., a gel) (10,(19)(20)(21)(22)(23)(24)(25) Modulation of Htt-NTF aggregation via polyphasic linkage2 separation are quantified in terms of saturation concentrations (14,19,26). For a given two-phase system, the saturation concentration is the bulk concentration of the protein beyond which the solution separates into two coexisting phases. The lower the saturation concentration, t...

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“…The discovery of the ROCK inhibitors in the context of aggregation allowed the characterization of the ROCK‐profilin signaling pathway . The FDA‐approved ROCK inhibitor HA‐1077 was shown to rescue retinal degeneration in the R6/2 mouse model of HD, showing that ROCK signaling inhibition is an HD‐relevant mechanistic pathway . With the same strategy, the group screened a set of biologically active compounds and found hits capable of inhibiting the aggregation of a pure polyQ stretch in HEK293 cells, suggesting these compounds as essential tools for understanding and counteracting the aggregation mechanisms in polyQ diseases.…”

Section: Therapeutic Strategies For Polyq Diseasesmentioning

confidence: 99%

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Duarte‐Silva

Maciel

2016

Medicinal Research Reviews

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Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.

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Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease

Cited by 43 publications

References 37 publications

Optical coherence tomography findings in Huntington’s disease: a potential biomarker of disease progression

Optical coherence tomography findings in Huntington’s disease: a potential biomarker of disease progression

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

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