Table 1.
Proposed normal HTT functions
| Proposed Function | Mechanism | References |
| Microtubule-based transport | HTT, together with HAP1 and the p150Glued subunit of dynactin, associate with the dynein motor complex involved in retrograde transport in neurons [81–85]. HTT can also interact directly with the dynein intermediate chain [85]. In addition, HAP1 interacts with kinesin light chain-1, a subunit of the kinesin anterograde motor complex [86]. Phosphorylation of the HAP1A isoform reduces its association with both p150Glued and kinesin light chain-1 [87], while phosphorylation of HTT at S421 favors recruitment of the kinesin-1 heavy chain to microtubules and vesicles or organelles for anterograde transport in a motor complex containing HTT, dynein, dynactin, and kinesin [88]. Upon de-phosphorylation of HTT S421, the kinesin-1 motor is released and the remaining complex with HTT favors retrograde transport [88]. | Li, S.-H. et al., 1998 [81] |
| Li, X.-J. et al., 1995 [82] | ||
| Engelender, S. et al., 1997 [83] | ||
| Block-Galarza et al., 1997 [84] | ||
| Caviston, J.P. et al., 2007 [85] | ||
| McGuire, J.R. et al., 2006 [86] | ||
| Rong, J. et al., 2006 [87] | ||
| Colin, E. et al., 2008 [88] | ||
| F-actin-based trafficking | HTT regulates clathrin-mediated endocytosis via several HTT-interacting proteins and their interactions with the actin cytoskeleton [89–95]. HTT forms a complex with HAP40 and Rab5 that can regulate both the long-range movement of early endosomes on microtubules and their localized movements on actin filaments [96, 97]. The mechanism facilitating early endosome movement along F-actin likely involves HTT’s interactions with OPTN (FIP2) [98, 99]. OPTN is a coiled-coil vesicle cargo adapter protein that could link the HTT-HAP40-Rab5 complex on early endosomes with the actin motor, myosin VI [99]. OPTN co-localizes with HTT and Rab8 within the Golgi complex, where it recruits myosin VI to the Golgi [100]. This interaction is hypothesized to contribute to post-Golgi trafficking to either the cell surface or the lysosome. The HTT-OPTN-Rab8 complex can also modulate cell polarization and the cell stress response [98]. | Rao, D.S. et al., 2001 [89] |
| Waelter, S. et al., 2001 [90] | ||
| Singaraja, R.R. et al., 2002 [91] | ||
| Yanai, A. et al., 2006 [92] | ||
| Kaltenbach, L.S. et al., 2007 [93] | ||
| Moreira Sousa, C. et al., 2013 [94] | ||
| El-Daher, M.T. et al., 2015 [95] | ||
| Pal, A. et al., 2008 [96] | ||
| Pal, A. et al., 2006 [97] | ||
| Hattula, K. and Peranen, J., 2000 [98] | ||
| Caviston, J.P. and Holzbaur, E.L., 2009 [99] | ||
| Sahlender, D.A. et al., 2005 [100] | ||
| Rab11 function and the trafficking of other Rab proteins | HTT can be found in a complex that activates Rab11, and is important for the trafficking of Rab11 vesicles [101, 102]. HTT’s activation of Rab11 contributes to the trafficking of recycling endosomes that help to establish apical polarity during epithelial morphogenesis in the mammary gland [103]. HTT, via Rab11 activation, regulates N-cadherin trafficking that is involved in the transition of newly born neurons from a multipolar to bipolar morphology during their migration [31]. HTT has also been proposed to act as a scaffold for Rab11’s regulation of GLUT3 expression on the neuronal cell surface [104]. Knock-down of Drosophila HTT expression affects the transport of Rab3, Rab19, Rab7, Rab2, and Rab8 vesicles [105]. | Li, X. et al., 2008 [101] |
| Power, D. et al., 2012 [102] | ||
| Elias, S. et al., 2015 [103] | ||
| Barnat, M. et al., 2017 [31] | ||
| McClory, H. et al., 2014 [104] | ||
| White, J.A. et al., 2015 [105] | ||
| BDNF transport | HTT enhances the efficiency of both anterograde and retrograde microtubule-based vesicular transport of BDNF via its association with HAP1 and p150Glued [106]. In the brain, BDNF is anterogradely transported in cortical projection neurons to the striatum where HTT also facilitates vesicular transport of TrkB in striatal neurons [107]. | Gauthier, L.R. et al., 2004 [106] |
| Liot, G. et al., 2013 [107] | ||
| Ciliogenesis | The HTT-HAP1 interaction contributes to primary cilia formation and is also required for the formation of the motile cilia found on ependymal cells lining the brain ventricles. Formation of cilia requires trafficking of protein components to the pericentriolar material (PCM) that surrounds that centrioles that both anchor and nucleate the microtubules in cilia. In the absence of HTT expression, PCM1, a major component of the PCM, together with pericentrin and ninein, are dispersed from the PCM, and cilia do not form properly [27]. Morpholino knock-down of Xenopus HTT in embryos results in reduced numbers and lengths of cilia on the cells covering the embryo’s epidermis [29]. | Keryer et al., 2011 [27] |
| Haremaki, T. et al., 2015 [29] | ||
| Transcription and chromatin modification | In early embryogenesis, Htt regulates polycomb repressor complex 2 function as a chromatin repressor that is important for normal Hox gene expression, extraembryonic trophoblast differentiation, and normal histone methylation [108]. HTT interacts with REST/NRSF in the cytosol to help maintain neuronal gene expression, including BDNF expression [109]. HTT also interacts with the cAMP Response Element Binding Protein (CBP), a protein involved in the regulation of histone acetylation and deacetylation [110], and regulates the transcription of nuclear receptors [111]. Loss of Htt expression in mouse embryonic fibroblasts affects the expression of genes involved in multiple pathways, including protein degradation, lipid metabolism, cell division, development, and extracellular matrix composition [112]. | Seong, I.S. et al., 2010 [108] |
| Zuccato, C. et al., 2003 [109] | ||
| Steffan, J.S. et al., 2000 [110] | ||
| Futter, M. et al., 2009 [111] | ||
| Zhang, H. et al., 2008 [112] | ||
| Post-transcriptional gene expression regulation | HTT participates in Processing (P)-body formation, RNA transport, and RNA translation; Htt interacts with Argonaut 2 (Ago2) in P-bodies that are involved in post-transcriptional gene silencing [113]. When Htt expression is reduced, mRNA transport is also inhibited, and Htt co-localizes with β-actin, BDNF, the microtubule-dependent anterograde motor protein Kif5a, dynein heavy chain (Dhc), and its own mRNA [114, 115]. Htt interacts with a variety of RNA binding proteins [44]. | Savas, J.N. et al., 2008 [113] |
| Ma, B. et al., 2011 [114] | ||
| Culver, B.P. et al., 2016 [115] | ||
| Culver, B.P. et al., 2012 [44] | ||
| Neurogenesis | HTT associates with centrosomes in neuronal progenitors undergoing cell division where it regulates mitotic spindle orientation [28, 116]. Htt is also required for the morphogenesis and migration of newly born cortical neurons [31]. In Xenopus, loss of htt expression disrupts development of the mandibular branch of the trigeminal nerve [28]. In zebrafish, htt contributes to the formation of the anterior neural plate that will eventually become the telencephalon [29]. In both mice and zebrafish, Htt is required for homotypic interactions between neuroepithelial cells during neurulation [117]. | Godin, J.D. et al., 2010 [28] |
| Godin, J.D. and Humbert, S., 2011 [116] | ||
| Barnat, M. et al., 2017 [31] | ||
| Haremaki, T. et al., 2015 [29] | ||
| Henshall, T.L. et al., 2009 [30] | ||
| Lo Sardo, V. et al., 2012 [117] | ||
| Synaptogenesis and synaptic plasticity | In the absence of Htt expression, excess excitatory corticostriatal and thalamostriatal synapses are generated in mice [32]. In Aplysia, ApHTT is located in both pre- and post-synaptic sensory neurons where it participates in long-term facilitation [8]. | McKinstry, S.U. et al., 2014 [32] |
| Choi, Y.B. et al., 2014 [8] | ||
| Signaling pathways | HTT interacts with epidermal growth factor (EGF) receptor signaling complexes containing Grb2 and RasGAP [118]. Screens for HTT-interacting proteins have identified proteins enriched in mTOR and Rho GTPase signaling. In addition, HTT-interacting proteins also participate in the oxidative stress response [93]. | Liu, Y.F. et al., 1997 [118] |
| Kaltenbach, L.S. et al., 2007 [93] | ||
| Cell stress responses and cell survival | HTT can influence cell death pathways through the regulation of Bcl-2-mediated Caspase3/9 activity [119, 120], and through the modulation of the interaction between the anti-apoptotic Huntingtin-interacting protein-1 (HIP-1) and its pro-apoptotic partner, Hippi [121, 122]. HTT is also required for both the rapid cell stress response and the canonical cell stress response pathways [51, 123]. The HTT N-terminal N17 domain plays a critical role in these processes, along with acting as an ROS sensor [56]. | Rigamonti, D. et al., 2000 [119] |
| Rigamonti, D. et al., 2001 [120] | ||
| Cheng, C.M. et al., 2003 [121] | ||
| Gervais, F.G. et al., 2002 [122] | ||
| Nath, S. et al., 2015 [51] | ||
| Munsie, L.N. and Truant, R., 2012 [123] | ||
| DiGiovanni, L.F. et al., 2016 [56] | ||
| Selective macroautophagy | HTT participates in stress-activated selective macroautophagy [58, 59, 124] and is required for the efficient transport of autophagosomes on microtubules [68]. | Ochaba, J. et al., 2014 [59] |
| Rui, Y.N. et al., 2015 [60] | ||
| Rui, Y.N. et al., 2015 [124] | ||
| Wong, Y.C. and Holzbaur, E.L., 2014 [68] | ||
| DNA damage repair | In response to DNA damage, HTT is phosphorylated at S1181 and S1201 by Cdk5 kinase [45]. Inhibiting this phosphorylation accelerates p53-dependent neuronal cell death when DNA damage is present. HTT also participates in base excision repair as part of a complex with the ataxia-talengiectasia mutated protein (ATM) [50]. | Anne, S.L. et al., 2007 [45] |
| Maiuri, T. et al., 2017 [50] |