mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington’s Disease

Ast, Anne; Buntru, Alexander; Schindler, Franziska; Hasenkopf, Regine; Schulz, Aline; Brusendorf, Lydia; Klockmeier, Konrad; Grelle, Gerlinde; McMahon, Benjamin H.; Niederlechner, Hannah; Jansen, Isabelle; Diez, Lisa; Edel, Juliane; Boeddrich, Annett; Franklin, Sophie A.; Baldo, Barbara; Schnoegl, Sigrid; Kunz, Séverine; Purfürst, Bettina; Gaertner, Annette; Kampinga, Harm H.; Morton, A. Jennifer; Petersén, Åsa; Kirstein, Janine; Bates, Gillian P.; Wanker, Erich E.

doi:10.1016/j.molcel.2018.07.032

Cited by 53 publications

(72 citation statements)

References 66 publications

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“…2F). We previously reported that Htt ex1 Q25-YFP aggregates formed in the glial cytoplasm co-localized with a similarly smaller-sized subpopulation of Htt ex1 Q91-mCherry aggregates from DA1 ORN axons (Pearce et al, 2015), and smaller mHtt ex1 aggregates are associated with increased seeding-propensity and neurotoxicity in other HD models (Ast et al, 2018; Chen et al, 2001). Taken together, these findings strongly suggest that Htt ex1 Q91-mCherry aggregates formed in presynaptic ORNs gain access to the cytoplasm of postsynaptic PNs to effect prion-like conversion of Htt ex1 Q25-GFP, and that Htt ex1 Q91-mCherry aggregate transmissibility is inversely correlated with aggregate size.…”

Section: Resultsmentioning

confidence: 98%

“…Draper could also selectively deplete a subpopulation of larger neuronal aggregates from which smaller transmissible species are produced. Interestingly, seeding propensity is correlated with smaller mHtt ex1 aggregate size in other HD models (Ast et al, 2018; Chen et al, 2001), and secondary nucleation processes initiated by aggregate fragmentation are thought to drive amplification of prion-like particles in many neurodegenerative diseases (Knowles et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, wtHtt proteins containing polyQ≤36 tracts only aggregate upon nucleation by pre-formed Htt aggregate “seeds” (Chen et al, 2001; Preisinger et al, 1999). A growing body of evidence from cell culture (Chen et al, 2001; Costanzo et al, 2013; Holmes et al, 2013; Ren et al, 2009; Sharma and Subramaniam, 2019; Trevino et al, 2012) and in vivo (Ast et al, 2018; Babcock and Ganetzky, 2015; Jeon et al, 2016; Masnata et al, 2019; Pearce et al, 2015; Pecho-Vrieseling et al, 2014) models of HD supports the idea that pathogenic mHtt aggregates have prion-like properties— they transfer from cell to cell and template the conformational change of soluble wtHtt proteins. Here, we report that mHtt aggregates formed in presynaptic olfactory receptor neuron (ORN) axons effect prion-like conversion of wtHtt proteins expressed in the cytoplasm of their postsynaptic partner projection neurons (PNs) in the adult fly olfactory system.…”

Section: Introductionmentioning

confidence: 99%

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Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

Donnelly

DeLorenzo

Zaya

et al. 2019

Preprint

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14Emerging evidence supports the hypothesis that pathogenic protein aggregates associated with 15 many neurodegenerative diseases spread from cell to cell through the brain in a manner akin to 16 infectious prions. Here, we show that mutant huntingtin (mHtt) aggregates associated with Huntington 17 disease transfer anterogradely from presynaptic to postsynaptic neurons in the adult Drosophila 18 olfactory system. Trans-synaptic transmission of mHtt aggregates is inversely correlated with neuronal 19 activity and blocked by caspase inhibition in presynaptic neurons, implicating synaptic dysfunction and 20 cell death in aggregate spreading. Remarkably, mHtt aggregate transmission across synapses requires 21 the scavenger receptor Draper and involves a transient visit to the glial cytoplasm, indicating that 22 phagocytic glia act as obligatory intermediates in aggregate spreading between synaptically-connected 23 neurons. These findings expand our understanding of phagocytic glia as double-edged players in 24 neurodegeneration-they clear neurotoxic protein aggregates, but also provide opportunities for prion-25 like seeds to evade phagolysosomal degradation and propagate further in the brain. 26 93 5 RESULTS 94Anterograde transfer of prion-like mHtt aggregates across synapses in the adult fly olfactory system 95 Aggregates formed by N-terminal fragments of mHtt generated by aberrant splicing (e.g., exon 96 1; Httex1) (Sathasivam et al., 2013) or caspase cleavage (e.g., exon 1-12; Httex1-12) (Graham et al., 2006) 97 (Fig. 1A) accumulate in HD patient brains, are highly cytotoxic, and spread between cells in culture and 98 in vivo (Babcock and Ganetzky, 2015; Costanzo et al., 2013; Pearce et al., 2015; Pecho-Vrieseling et 99 al., 2014; Ren et al., 2009). We have previously established transgenic Drosophila that employ binary 100 expression systems [e.g., Gal4-UAS, QF-QUAS, or LexA-LexAop (Riabinina and Potter, 2016)] to 101 express fluorescent protein (FP) fusions of Httex1 in non-overlapping cell populations in order to monitor 102 cell-to-cell transfer of mHttex1 aggregates in intact brains (Donnelly and Pearce, 2018; Pearce et al., 103 2015). Our experimental approach (Fig. 1B) exploits the fact that wtHttex1 proteins only aggregate upon 104 encountering mHttex1 aggregate seeds (Chen et al., 2001; Preisinger et al., 1999), such that transfer of 105 mHttex1 aggregates from "donor" cells is reported by conversion of cytoplasmic wtHttex1 from its normally 106 soluble, diffuse state to a punctate, aggregated state in "acceptor" cells. To confirm that mHttex1 107 nucleates the aggregation of wtHttex1 in fly neurons, we co-expressed FP-fusions of these two proteins 108 using pan-neuronal elav[C155]-Gal4. In flies expressing only mCherry-tagged mHttex1 (Httex1Q91-109 mCherry) pan-neuronally, aggregates were visible as discrete mCherry+ puncta throughout neuronal 110 cell bodies and neuropil regions of adult fly brains ( Fig. 1-figure supplement 1A). By contrast, GFP-111 tagged wtHttex1 (Httex1Q25-GFP) was expressed di...

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

Donnelly

DeLorenzo

Zaya

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Apart from full‐length mHTT, truncated N‐terminal polyQ‐containing fragments may also play a critical role in HD (Davies et al ; Ast et al ). The mHTTex1 fragment has been reported to efficiently self‐assemble into higher order structures such as spherical oligomers or amyloid fibrils in vitro and in vivo (Sathasivam et al ; Sahoo et al ; Wagner et al ).…”

Section: Various Putatively Pathogenic Mhtt Protein Species Have Beenmentioning

confidence: 99%

“…Recent studies from different laboratories demonstrated that polyQ‐expanded mHTTex1 fibrils, rather than oligomers or misfolded monomers exert toxicity in HD (Drombosky et al ). Minute amounts of small self‐propagating HTTex1Q97 fibrils in neurons were shown to be sufficient to dramatically shorten the life‐span of HD transgenic flies (Ast et al ). Here, it is important to note that misfolded mHTTex1 monomers and oligomers are structurally distinct from amyloid fibrils.…”

Section: Various Putatively Pathogenic Mhtt Protein Species Have Beenmentioning

confidence: 99%

The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

Wanker

Ast

Schindler

et al. 2019

Journal of Neurochemistry

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Mutations are at the root of many human diseases. Still, we largely do not exactly understand how they trigger pathogenesis. One, more recent, hypothesis has been that they comprehensively perturb protein-protein interaction (PPI) networks and significantly alter key biological processes. Under this premise, many rare genetic disorders with Mendelian inheritance, like Huntington's disease and several spinocerebellar ataxias, are likely to be caused by complex genotype-phenotype relationships involving abnormal PPIs. These altered PPI networks and their effects on cellular pathways are poorly understood at the molecular level. In this review, we focus on PPIs that are perturbed by the expanded pathogenic polyglutamine tract in huntingtin (HTT), the protein which, in its mutated form, leads to the autosomal dominant, neurodegenerative Huntington's disease. One aspect of perturbed mutant HTT interactions is the formation of abnormal protein species such as fibrils or large neuronal inclusions as a result of homotypic and heterotypic aberrant molecular interactions. This review focuses on abnormal PPIs that are associated with the assembly of mutant HTT aggregates in cells and their potential relevance in disease. Furthermore, the mechanisms and pathobiological processes that may contribute to phenotype development, neuronal dysfunction and toxicity in Huntington's disease brains are also discussed.

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Progressive alterations in white matter microstructure across the timecourse of Huntington's disease

et al. 2023

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Background Whole‐brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD). Methods We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden. The TrackOn‐HD study included 67 controls, 67 premanifest, and 10 early manifest HD (baseline and 24‐month data); the PADDINGTON study included 33 controls and 49 early manifest HD (baseline and 15‐month data). Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity from baseline to last study visit were investigated for each cohort using tract‐based spatial statistics. An optimized pipeline was employed to generate participant‐specific templates to which diffusion tensor imaging maps were registered and change maps were calculated. We examined longitudinal differences between HD expansion‐carriers and controls, and correlations with clinical scores, including the composite UHDRS (cUHDRS). Results HD expansion‐carriers from TrackOn‐HD, with lower disease burden, showed a significant longitudinal decline in FA in the left superior longitudinal fasciculus and an increase in MD across subcortical WM tracts compared to controls, while in manifest HD participants from PADDINGTON, there were significant widespread longitudinal increases in diffusivity compared to controls. Baseline scores in clinical scales including the cUHDRS predicted WM microstructural change in HD expansion‐carriers. Conclusion The present study showed significant longitudinal changes in WM microstructure across the HD timecourse. Changes were evident in larger WM areas and across more metrics as the disease advanced, suggesting a progressive alteration of WM microstructure with disease evolution.

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mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington’s Disease

Cited by 53 publications

References 66 publications

Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

Progressive alterations in white matter microstructure across the timecourse of Huntington's disease

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