Coiled-coil structure-dependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects

Kwon, Min Jee; Han, Myeong Hoon; Bagley, Joshua A.; Hyeon, Do Young; Ko, Byung Su; Lee, Yun Mi; Jun, In; Kim, Seung Yeol; Kim, Dong Young; Kim, Ho Min; Hwang, Daehee; Lee, Sung Bae; Jan, Yuh Nung

doi:10.1073/pnas.1807206115

Cited by 32 publications

(45 citation statements)

References 43 publications

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“…The model suggests that as concentrations of ApCPEB increase, as could occur in highly concentrated LLPS organelles (Ford et al, 2019), coiled-coil ApCPEB is poised to form β-sheet-rich structures in the upstream polyQ region (Chen et al, 2016). Remarkably, this model fits within the known mechanisms of neurodegenerative Huntingtin amyloidogenesis (Fiumara et al, 2010), spinocerebellar ataxia SCA3 amyloidogenesis (Kwon et al, 2018), and cleidocranial dysplasia RUNX2 aggregation and toxicity (Pelassa et al, 2014).…”

Section: Coiled Coil To β-Sheet Conversionmentioning

confidence: 53%

Coiled-Coil Motifs of RNA-Binding Proteins: Dynamicity in RNA Regulation

Ford

Fioriti

2020

Front. Cell Dev. Biol.

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Neuronal granules are biomolecular condensates that concentrate high quantities of RNAs and RNA-related proteins within neurons. These dense packets of information are trafficked from the soma to distal sites rich in polysomes, where local protein synthesis can occur. Movement of neuronal granules to distal sites, and local protein synthesis, play a critical role in synaptic plasticity. The formation of neuronal granules is intriguing; these granules lack a membrane and instead phase separate due to protein and RNA interactions. Low complexity motifs and RNA binding domains are highly prevalent in these proteins. Here, we introduce the role that coiled-coil motifs play in neuronal granule proteins, and investigate the structure-function relationship of coiled-coil proteins in RNA regulation. Interestingly, low complexity domains and coiled-coil motifs are highly dynamic, allowing for increased functional response to environmental influences. Finally, biomolecular condensates have been suggested to drive the formation of toxic, neurodegenerative proteins such as TDP-43 and tau. Here, we review the conversion of coiled-coil motifs to amyloid structures, and speculate a role that neuronal granules play in coiled-coil to amyloid conversions of neurodegenerative proteins.

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Section: Coiled Coil To β-Sheet Conversionmentioning

confidence: 53%

Coiled-Coil Motifs of RNA-Binding Proteins: Dynamicity in RNA Regulation

Ford

Fioriti

2020

Front. Cell Dev. Biol.

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“…Our finding of agedependent increase of ThS + Htt aggregates directly marks the accumulation of adhesive and toxic β-structures. Notably, other structures, such as coiled-coil structures in polyQ proteins, also confer neuronal toxicity through sequestration of target proteins (65).…”

Section: Discussionmentioning

confidence: 99%

Nmnat restores neuronal integrity by neutralizing mutant Huntingtin aggregate-induced progressive toxicity

Tao

Brazill

et al. 2019

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

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Accumulative aggregation of mutant Huntingtin (Htt) is a primary neuropathological hallmark of Huntington’s disease (HD). Currently, mechanistic understanding of the cytotoxicity of mutant Htt aggregates remains limited, and neuroprotective strategies combating mutant Htt-induced neurodegeneration are lacking. Here, we show that in Drosophila models of HD, neuronal compartment-specific accumulation of mutant Htt aggregates causes neurodegenerative phenotypes. In addition to the increase in the number and size, we discovered an age-dependent acquisition of thioflavin S+, amyloid-like adhesive properties of mutant Htt aggregates and a concomitant progressive clustering of aggregates with mitochondria and synaptic proteins, indicating that the amyloid-like adhesive property underlies the neurotoxicity of mutant Htt aggregation. Importantly, nicotinamide mononucleotide adenylyltransferase (NMNAT), an evolutionarily conserved nicotinamide adenine dinucleotide (NAD+) synthase and neuroprotective factor, significantly mitigates mutant Htt-induced neurodegeneration by reducing mutant Htt aggregation through promoting autophagic clearance. Additionally, Nmnat overexpression reduces progressive accumulation of amyloid-like Htt aggregates, neutralizes adhesiveness, and inhibits the clustering of mutant Htt with mitochondria and synaptic proteins, thereby restoring neuronal function. Conversely, partial loss of endogenous Nmnat exacerbates mutant Htt-induced neurodegeneration through enhancing mutant Htt aggregation and adhesive property. Finally, conditional expression of Nmnat after the onset of degenerative phenotypes significantly delays the progression of neurodegeneration, revealing the therapeutic potential of Nmnat-mediated neuroprotection at advanced stages of HD. Our study uncovers essential mechanistic insights to the neurotoxicity of mutant Htt aggregation and describes the molecular basis of Nmnat-mediated neuroprotection in HD.

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“…In addition, FoxOs were found to be upregulated in aged brains and function to delay aging-related axonal tract degeneration by suppressing mTor activity (Hwang et al, 2018). In Drosophila C4da neurons, FoxO was previously found to promote dendrite space-filling and to mediate polyQ-induced neuronal toxicity (Sears and Broihier, 2016; Kwon et al, 2018). However, FoxO expression patterns in neural and non-neural tissues have not been compared and whether neuronal function of FoxO is related to nutrition was previously unknown.…”

Section: Discussionmentioning

confidence: 99%

Low FoxO expression inDrosophilasomatosensory neurons protects dendrite growth under nutrient restriction

Poe

Zhang

et al. 2019

Preprint

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17During prolonged nutrient restriction, developing animals redistribute vital nutrients to favor brain 18 growth at the expense of other organs. In Drosophila, such brain sparing relies on a glia-derived growth 19 factor to sustain proliferation of neural stem cells. However, whether other aspects of neural 20 development are also spared under nutrient restriction is unknown. Here we show that dynamically 21 growing somatosensory neurons in the Drosophila peripheral nervous system exhibit organ sparing at 22 the level of arbor growth: Under nutrient stress, sensory dendrites preferentially grow as compared to 23 neighboring non-neural tissues, resulting in dendrite overgrowth. Underlying this neuronal nutrient-24 insensitivity is the lower expression of the stress sensor FoxO in neurons. Consequently, nutrient 25 restriction suppresses Tor signaling less and does not induce autophagy in neurons. Preferential dendrite 26 growth is functional desirable because it results in heightened animal responses to sensory stimuli, 27 indicative of a potential survival advantage under environmental challenges.28

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Coiled-coil structure-dependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects

Cited by 32 publications

References 43 publications

Coiled-Coil Motifs of RNA-Binding Proteins: Dynamicity in RNA Regulation

Coiled-Coil Motifs of RNA-Binding Proteins: Dynamicity in RNA Regulation

Nmnat restores neuronal integrity by neutralizing mutant Huntingtin aggregate-induced progressive toxicity

Low FoxO expression inDrosophilasomatosensory neurons protects dendrite growth under nutrient restriction

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