Unconventional Secretion and Intercellular Transfer of Mutant Huntingtin

Tang, Bor Luen

doi:10.3390/cells7060059

Cited by 25 publications

(18 citation statements)

References 149 publications

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“…While free plasma is a source of mHTT, soluble protein was also detected in all tested immune cells. These cells could have released mHTT into the organs via multiple pathways including through exocytosis [28] or the release of extracellular vesicles [58]. Previous evidence has demonstrated that both exocytosis and extracellular vesicles can contribute to mHTT spreading in HD.…”

Section: Discussionmentioning

confidence: 99%

Shedding a new light on Huntington’s disease: how blood can both propagate and ameliorate disease pathology

et al. 2020

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Huntington's disease (HD) is a monogenic neurodegenerative disorder resulting from a mutation in the huntingtin gene. This leads to the expression of the mutant huntingtin protein (mHTT) which provokes pathological changes in both the central nervous system (CNS) and periphery. Accumulating evidence suggests that mHTT can spread between cells of the CNS but here, we explored the possibility that mHTT could also propagate and cause pathology via the bloodstream. For this, we used a parabiosis approach to join the circulatory systems of wild-type (WT) and zQ175 mice. After surgery, we observed mHTT in the plasma and circulating blood cells of WT mice and post-mortem analyses revealed the presence of mHTT aggregates in several organs including the liver, kidney, muscle and brain. The presence of mHTT in the brain was accompanied by vascular abnormalities, such as a reduction of Collagen IV signal intensity and altered vessel diameter in the striatum, and changes in expression of Glutamic acid decarboxylase 65/67 (GAD65-67) in the cortex. Conversely, we measured reduced pathology in zQ175 mice by decreased mitochondrial impairments in peripheral organs, restored vessel diameter in the cortex and improved expression of Dopamine-and cAMP-regulated phosphoprotein 32 (DARPP32) in striatal neurons. Collectively, these results demonstrate that circulating mHTT can disseminate disease, but importantly, that healthy blood can dilute pathology. These findings have significant implications for the development of therapies in HD.

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Section: Discussionmentioning

confidence: 99%

Shedding a new light on Huntington’s disease: how blood can both propagate and ameliorate disease pathology

et al. 2020

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“…6 A ). In manifest HD, lysosomal function and autophagy become impaired with aging in association with polyQ expansion of HTT and reduced HTT protein levels (31, 45), resulting in reduced full-length HTT phosphorylation, and mutant HTT exon 1 protein and other autophagy cargos accumulate and aggregate, or may be expelled from the cell for prion-like propagation to neighboring cells (46–48). The ensuing cellular stress causes a robust microglial activation (49) and inflammatory pathway induction and accumulation of IKKβ that can no longer activate autophagy (13), resulting in cellular dysfunction and neurodegeneration (Fig.…”

Section: Discussionmentioning

confidence: 99%

IKKβ slows Huntington’s disease progression in R6/1 mice

Ochaba

Fote

Kachemov

et al. 2019

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

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Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington’s disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.

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“…In the case of HTT, several mechanisms have been proposed, including extracellular vesicles (Tang, 2018) and transneuronal (synaptic) spreading (Pecho‐Vrieseling et al , 2014). Our early work has also shown the intercellular propagation of mHTT through TNTs (Costanzo et al , 2013).…”

Section: An Overview Of Tunneling Nanotubesmentioning

confidence: 99%

Peering into tunneling nanotubes—The path forward

Cervantes

Zurzolo

2021

The EMBO Journal

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The identification of Tunneling Nanotubes (TNTs) and TNT‐like structures signified a critical turning point in the field of cell‐cell communication. With hypothesized roles in development and disease progression, TNTs’ ability to transport biological cargo between distant cells has elevated these structures to a unique and privileged position among other mechanisms of intercellular communication. However, the field faces numerous challenges—some of the most pressing issues being the demonstration of TNTs in vivo and understanding how they form and function. Another stumbling block is represented by the vast disparity in structures classified as TNTs. In order to address this ambiguity, we propose a clear nomenclature and provide a comprehensive overview of the existing knowledge concerning TNTs. We also discuss their structure, formation‐related pathways, biological function, as well as their proposed role in disease. Furthermore, we pinpoint gaps and dichotomies found across the field and highlight unexplored research avenues. Lastly, we review the methods employed to date and suggest the application of new technologies to better understand these elusive biological structures.

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Unconventional Secretion and Intercellular Transfer of Mutant Huntingtin

Cited by 25 publications

References 149 publications

Shedding a new light on Huntington’s disease: how blood can both propagate and ameliorate disease pathology

Shedding a new light on Huntington’s disease: how blood can both propagate and ameliorate disease pathology

IKKβ slows Huntington’s disease progression in R6/1 mice

Peering into tunneling nanotubes—The path forward

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