Table 1.
In vitro evidence of mHTT spreading capacities.
| Mechanism | Protein form | Cell model | Observations | References |
|---|---|---|---|---|
| Transynaptic propagation | Endogenous mHTT from R6/2 mice | Ex vivo mixed cortico-striatal cultures from R6/2 or wild type mice | Propagation of mHTT from R6/2 cortical to wild-type striatal neurons Significant vulnerability of striatal neurons in comparison to cortical neurons | Pecho-Vrieseling et al., 2014 |
| Endogenous mHTT from R6/2 mice | Human ESCs and human iPSC differentiated into neurons transplanted into organotypic brain slices of R6/2 mice | Propagation of endogenous mHTT from murine host tissue to grafted hGFP neurons followed by progressive neurodegeneration of recipient hGFP neurons | ||
| TNTs | Transfection with GFP-480-68Q (donor); mCherry (acceptor) | Co-culture of CAD transfected cells (68Q or mCherry) Co-culture of transfected primary CGNs (68Q or mCherry) | Transfer of GFP-480-68Q to both CAD and CGN neuronal cells via TNTs | Costanzo et al., 2013 |
| Vesicular transport | ||||
| Exosome | HD143F-derived exosomes | Co-culture of HD143F and NSCs | Spread of mHTT from HD143F to NSCs | Jeon et al., 2016 |
| NSCs exposed to HD143F-derived exosomes | Spread of exosomes-containing mHTT in NSCs | |||
| Exopher | Genetically-engineered expression of Q128 | C. elegans | Q128 gene expression increases the production of exophers Exopher content, including organelles, protein and mHTT, is found in remote cells of the C. elegans | Melentijevic et al., 2017 |
| Endocytosis | Fibrillar Alexa488-HTTExon1Q44 and/or polyQ44 | Undifferentiated and differentiated mouse and human neuroblastoma cells (N2A and SH-SY5Y) | Internalization and intracellular localization of HTTExon1Q44 and PQ44 fibrils in both types of neuroblastoma cells Fibrillar HTTExon1Q44 uptake via clathrin-dependent endocytosis No mechanisms evaluated for PQ44 fibrils | Ruiz-Arlandis et al., 2016 |
| Direct penetration of plasma membrane | Synthetic K2Q44K2 fibrils | HEK; HeLa; Cos-7; CHO; N2A | Breach plasma membranes by K2Q44K2 fibrils in all cell types tested | Ren et al., 2009 |
| Transfection with ChFP-HTTQ25 and synthetic K2Q44K2 fibrils | HEK | Recruitment of soluble HTT forms into IBs by synthetic K2Q44K2 fibrils in transfected HEK cells | ||
| Chemically synthesized Q42, NLS-Q42 and NLS-Q20 fibrils | Cos-7; PC-12 | In the nuclei, smaller aggregates are more toxic than larger ones in both cell types tested | Yang et al., 2002 | |
| Unknown | Transfection with 25/103QHTT-V1 and 25/103QHTT-V2 | Co-culture of H4 cells expressing 103QHTT-V1 and HEK cells expressing 103QHTT-V2 | Polymerization and cell-to-cell transmission of HTT oligomers | Herrera et al., 2011 |
| Exposure to conditioned medium derived from GFP-mHTT-Q19 or GFP-mHTT-Q103 transfected HEK cells | SH-SY5Y cells | Presence of exogenous mHTT protein (Q19 and Q103) within recipient SH-SY5Y cells | Jeon et al., 2016 |
CAD, mouse catecholaminergic neuronal cell line; CGNs, cerebellar granule neurons; CHO, epithelial-like cell line from Chinese hamster ovary; Cos-7, fibroblast like cell lines derived from monkey kidney; ESCs, embryotic stem cells; H4, human brain neuroglioma cells; GFP, green fluorescent protein; HD, Huntington's disease; HD143F, human fibroblast derived from Huntington's disease patient carrying 143 polyglutamine repeats; HEK, human embryonic kidney cells; HeLa, human uterine cervical carcinoma cells; hGFP neurons, human GFP positive neurons; HTT, huntingtin; IBs, inclusion bodies; iPSC, induced pluripotent stem cells; mHTT, mutant huntingtin; NSCs, neural stem cells; N2A, mouse neuroblastoma cell line; NLS, nuclear localization signals; PC-12, cell line from pheomochromocytoma of the rat adrenal medulla; PolyQ, polyglutamine; SH-SY5Y, human neuroblastoma cell line; TNTs, Tunneling nanotubes; V1, Venus protein half; V2, Venus protein half 2.