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Intermediate Filament Protein Accumulation in Motor Neurons Derived from Giant Axonal Neuropathy Ipscs Rescued by Restoration Of

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Intermediate Filament Protein Accumulation in Motor Neurons Derived from Giant Axonal Neuropathy Ipscs Rescued by Restoration Of Human Molecular Genetics, 2015, Vol. 24, No. 5 1420–1431 doi: 10.1093/hmg/ddu556 Advance Access Publication Date: 4 November 2014 Original Article ORIGINAL ARTICLE Intermediate filament protein accumulation in motor neurons derived from giant axonal neuropathy iPSCs rescued by restoration of gigaxonin Bethany L. Johnson-Kerner1,2,3,4,†, Faizzan S. Ahmad10,‡,¶, Alejandro Garcia Diaz1, John Palmer Greene1, Steven J. Gray7, Richard Jude Samulski7, Wendy K. Chung6, Rudy Van Coster8, Paul Maertens9, Scott A. Noggle10, Christopher E. Henderson1,2,3,4,5, and Hynek Wichterle1,2,3,4,* 1Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA, 2Center for Motor Neuron Biology and Disease, 3Departments of Pathology and Cell Biology, Neurology, and Neuroscience, 4Columbia Stem Cell Initiative, 5Department of Rehabilitation and Regenerative Medicine, 6Department of Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10032, USA, 7Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 8Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium, 9Departments of Pediatric Neurology, University of South Alabama, Mobile, AL, USA, and 10New York Stem Cell Foundation, New York, NY 10032, USA *To whom correspondence should be addressed. Tel: +1 2123423929; Fax: +1 2123421555; Email: [email protected] Abstract Giant axonal neuropathy (GAN) is a progressive neurodegenerative disease caused by autosomal recessive mutations in the GAN gene resulting in a loss of a ubiquitously expressed protein, gigaxonin. Gene replacement therapy is a promising strategy for treatment of the disease; however, the effectiveness and safety of gigaxonin reintroduction have not been tested in human GAN nerve cells. Here we report the derivation of induced pluripotent stem cells (iPSCs) from three GAN patients with different GAN mutations. Motor neurons differentiated from GAN iPSCs exhibit accumulation of neurofilament (NF-L) and peripherin (PRPH) protein and formation of PRPH aggregates, the key pathological phenotypes observed in patients. Introduction of gigaxonin either using a lentiviral vector or as a stable transgene resulted in normalization of NEFL and PRPH levels in GAN neurons and disappearance of PRPH aggregates. Importantly, overexpression of gigaxonin had no adverse effect on survival of GAN neurons, supporting the feasibility of gene replacement therapy. Our findings demonstrate that GAN iPSCs provide a novel model for studying human GAN neuropathologies and for the development and testing of new therapies in relevant cell types. † Present address: Department of Pediatrics, University of California, San Francisco, 505 Parnassus Ave, M691, San Francisco, CA 94143, USA. ‡ Present address: Qatar Cardiovascular Research Center, Qatar Foundation, Qatar Science and Technology Park, Doha, Qatar. ¶ Present address: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. Received: September 20, 2014. Accepted: October 27, 2014. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] 1420 Human Molecular Genetics, 2015, Vol. 24, No. 5 | 1421 Introduction In this study, we successfully generated GAN iPSCs from three GAN patients and differentiated them in vitro into spinal motor Disorganization of the neurofilament (NF) network is a feature of neurons (iPSC-MNs), a cell type strongly affected in patients. several neurodegenerative disorders, including amyotrophic lat- Strikingly, the GAN iPSC-MNs exhibit the intermediate filament eral sclerosis, Parkinson’s disease and axonal Charcot–Marie– protein accumulation characteristic of patients at early stages Tooth disease (1,2). Patients with giant axonal neuropathy (GAN) of the disease. Importantly, the GAN phenotypes can be rescued provide a particularly striking example: peripheral nerve biopsies by gigaxonin replacement using either a lentiviral vector or stable show accumulations of NFs within enlarged axons (3), while the transgenesis, demonstrating that the phenotype is caused by intermediate filament desmin is seen to accumulate in muscle fi- GAN mutation. GAN iPSCs therefore faithfully recapitulate key bers, glial fibrillary acidic protein in astrocytes and vimentin in GAN phenotypes and will prove valuable tools for preclinical test- multiple cell types, including primary fibroblast biopsies from pa- ing of gene replacement therapy and biochemical and genetic tients (4,5). Patients with GAN present in their first decade with analysis of the disease process to identify additional therapeutic loss of motor and sensory function. Currently, there is no treat- targets. ment for GAN, and the life expectancy is typically <30 years. Whether NF accumulation in neurons contributes directly to the pronounced sensory and motor neuropathy that is a clinical hall- mark of GAN is not known, but pathological observations of axonal Results loss, enlarged axons with abnormally thin myelin sheaths, atro- GAN is a rare neurodegenerative disease with limited access to phy of the pyramidal tracts, swelling of some axons in the spinal patient samples. We were successful in obtaining skin biopsies roots and anterior horn cell loss in the cervical and lumbar regions from five patients who had either a confirmed mutation in GAN of the spinal cord would be consistent with a causal role (6–9). or a classical GAN phenotype in the absence of an identified mu- GAN is a rare autosomal recessive disease caused by muta- tation. To represent the clinical and genetic heterogeneity of the tions in a single gene, GAN, which encodes gigaxonin, a ubiqui- disease, samples were collected from GAN patients of different tously expressed cytoplasmic protein that has been postulated sex, age and mutation (Fig. 1A). We generated iPSCs from skin fi- to act as an E3 ligase substrate adaptor (10). To model GAN path- broblasts by transduction with retroviral vectors encoding OCT4, ology in the mouse, two loss-of-function approaches were SOX2, KLF4 and c-MYC as described (14). All iPSC lines were as- explored: deletion of either the promoter-exon1 region or exons sayed for formation of embryonic stem cell-like colonies with 3–5. The former did not develop any overt neurological defects well-delineated phase-bright margins (Fig. 1B), expression of nu- over 15 months (11). The latter strategy was adopted for three clear and surface markers characteristic of human stem cells Δ – GAN ex3 5 models. The first, published by Ding et al. (12), was re- (Fig. 1C and D), karyotype (Fig. 1E) and viral transgene expression ported to develop strong motor deficits as early as 6 months of (Fig. 1F and G). Several iPSC lines were generated from each pa- age, but the characterization was performed using a heteroge- tient (Table 1; the line number refers to the GAN patient, and Δ – neous genetic background (11). Subsequently, GAN ex3 5 models the letter refers to a particular iPSC clone). Lines from Patients 1 were made on pure 129/SvJ and C57BL/6 backgrounds, respectively and 4 were excluded because of inadequate morphology of col- (13). Despite the detectable accumulation of intermediate fila- onies, indicative of spontaneous differentiation or high persist- ments and the absence of gigaxonin at 48 weeks of age, the former ent transgene expression (Fig. 1F and G), but those from model shows only a mild motor impairment from 60 weeks on- Patients 2, 3 and 5 satisfied all criteria. One clone per Patient 2, ward and the latter a mild sensory impairment (13). The relatively 3 and 5 (iPSC lines 2E, 3X and 5L) was selected for subsequent de- mild sensorimotor phenotype seen in both cases raises the possi- tailed analysis. bility that gigaxonin engages in species-specific interactions and As a first step toward analyzing the effects of the GAN muta- functions that might more faithfully be modeled using human tions, we differentiated the three selected iPSC lines into motor cells. Mouse and human gigaxonin share 98% similarity, with neurons (iPSC-MNs)—as motor neuron axons are strongly af- amino acid variants in the BR-C, ttk and bab (BTB), BTB and C- fected in patients—using a 28-day embryoid body-based protocol terminal Kelch (BACK) and Kelch domains. It is unknown what (15) that generates iPSC-MNs with ∼20–30% efficiency (Fig. 2A). effect, if any, these amino acid variants have on the structure Microtubule-associated protein 2 (MAP2)-positive cells generated and function of human and mouse gigaxonin. from GAN iPSCs exhibited typical neuronal morphology (Fig. 2E) Successful derivation of induced pluripotent stem cells and expressed motor neuron markers HB9 and ISL1 at similar le- (iPSCs) (14,15) from patient skin fibroblasts provides an opportun- vels to a control iPSC line 18c (15) (Fig. 2F and data not shown). In ity to model the pathogenesis and treatment of human heritable addition, GAN neurons cultured for 12 days formed dense net- diseases in cell culture (16–21). Given the inaccessibility of pri- works of processes and exhibited abundant spontaneous Ca2+ mary human neurons, iPSCs present an appealing alternative. transients, demonstrating that they are functionally active Not only are patient mutations and genetic background faithfully (Fig. 2G). Patients with GAN have low, sometimes undetectable recapitulated in iPSCs, but neuronal differentiation protocols levels of gigaxonin protein (4). Similarly marked reductions allow for the production
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