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Frontiers in Biology

Front. Biol.    2016, Vol. 11 Issue (5) : 339-354     DOI: 10.1007/s11515-016-1416-0
Modeling axonal defects in hereditary spastic paraplegia with human pluripotent stem cells
Kyle R. Denton1,Chongchong Xu2,4,Harsh Shah3,Xue-Jun Li2,4()
1. Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA
2. Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, IL 61107, USA
3. MD program, College of Medicine at Rockford, IL 61107, USA
4. Department of Bioengineering, University of Illinois at Chicago, IL 60607, USA
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BACKGROUND: Cortical motor neurons, also known as upper motor neurons, are large projection neurons whose axons convey signals to lower motor neurons to control the muscle movements. Degeneration of cortical motor neuron axons is implicated in several debilitating disorders including hereditary spastic paraplegia (HSP). Since the discovery of the first HSP gene, SPAST that encodes spastin, over 70 distinct genetic loci associated with HSP have been identified. How the mutations of these functionally diverse genes result in axonal degeneration and why certain axons are affected in HSP remain largely unknown. The development of induced pluripotent stem cell (iPSC) technology has provided researchers an excellent resource to generate patient-specific human neurons to model human neuropathological processes including axonal defects.

METHODS: In this article, we will first review the pathology and pathways affected in the common forms of HSP subtypes by searching the PubMed database. We will then summarize the findings and insights gained from studies using iPSC-based models, and discuss challenges and future directions.

RESULTS: HSPs, a heterogeneous group of genetic neurodegenerative disorders, exhibit similar pathological changes that result from retrograde axonal degeneration of cortical motor neurons. Recently, iPSCs have been generated from several common forms of HSP including SPG4, SPG3A, and SPG11 patients. Neurons derived from HSP iPSCs exhibit impaired neurite outgrowth, increased axonal swellings, and reduced axonal transport, recapitulating disease-specific axonal defects.

CONCLUSIONS: These patient-derived neurons offer a unique tool to study the pathogenic mechanisms and explore the treatments for rescuing axonal defects in HSP, as well as other diseases involving axonopathy.

Keywords HSP      axonal degeneration      pluripotent stem cells      spastin      atlastin-1     
Corresponding Authors: Xue-Jun Li   
Online First Date: 28 September 2016    Issue Date: 04 November 2016
 Cite this article:   
Kyle R. Denton,Chongchong Xu,Harsh Shah, et al. Modeling axonal defects in hereditary spastic paraplegia with human pluripotent stem cells[J]. Front. Biol., 2016, 11(5): 339-354.
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Xue-Jun Li
Fig.1  Major pathways affected in HSP. Proteins involved in HSP have a wide range of cellular functions, however many of them cluster into several common cellular pathways. Spastin (for SPG4, the most common form of HSP) and atlastin-1 (for SPG3A, the most common early-onset form of HSP) are shown in red and discussed in detail. Modified from (Blackstone, 2012) with permission from the Annual Review of Neuroscience, Volume 35 by Annual Reviews.
Fig.2  Spastin isoforms and domains. The N terminus of the protein contains two domains important for protein–protein interactions, the hydrophobic region (HR) and the microtubule interacting and targeting (MIT) domains. The C terminus contains a microtubule binding domain (MBD) and an AAA ATPase domain, which allows spastin to interact and sever microtubules. Modified from (Blackstone et al., 2011) by permission from Macmillan Publishers Ltd: Nature Reviews Neuroscience, copyright 2011.
Fig.3  Atlasin-1 domains. Atlastin-1 consists of three main domains: the large GTPase domain, the middle linker domain, and two trans-membrane domains (TMDs). Each TMD partially inserts into ER lipid bilayers through hydrophobic wedging. At the C terminus is a KDEL ER retention (ERR) signal.
Fig.4  Establishment of iPSC-based SPG4 and SPG3A models that recapitulate disease-specific axonal phenotypes. (A, B) Immunostaining showing the expression of pluripotent protein NANOG and TRA-1-60 (A) by the iPSCs derived from a patient with intron 4 splice acceptor mutation (c.683-1G>T; panel B). (C) At 6 weeks after differentiation, telencephalic glutamatergic neurons (Tbr1+/βIII-tubulin+) were efficiently generated from WT (control) and SPG4 iPSCs. (D) Neurons derived from SPG4 iPSCs displayed swellings in Tau+ axons, while control neuron axons were mostly smooth with no swellings. (E, F) Increased formation of axonal swellings was also observed from telencephalic neurons derived from iPSCs of another patient with a C>T transition located in Exon 5 of the SPAST gene (amber mutation, E). (G) To examine fast axonal transport of mitochondria, cells were stained with MitoTracker Red CMXRos (Invitrogen). (H) Representative distance versus time kymographs over a 5 min recording. (I) Quantification of motile mitochondria in week 8 telencephalic neurons showed a significant decrease of motile mitochondria in SPG4 neurons compared to control neurons. Data presented as mean±SD. **P<0.01. (J) SPG3A fibroblast cells were successfully programmed to iPSCs that have typical ESC morphology. (K) As shown by the representative distance versus time kymographs, reduction of motile mitochondria was also observed in SPG3A iPSC-derived telencephalic neurons. Blue indicates Hoechst stained nuclei. Bars, 100 (A), 50 (C), 20 (D,F), 10 (G, H), and 5 (K) mm. Modified from references (Denton et al., 2014; Zhu et al., 2014).
Fig.5  Summary of major phenotypes observed in SPG4 and SPG3A iPSC-derived neurons. We observed length-dependent axonal swellings in SPG4 neurons, and neurite outgrowth abnormalities in SPG3A neurons. Reduced axonal transport was observed in both SPG4 and SPG3A neurons. These phenotypes were rescued following treatment with the microtubule-targeting drug vinblastine, linking alterations to microtubule dynamics in these forms of autosomal dominant HSP.
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