Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2023

Open Access 01-12-2023 | Spastic Paraplegia | Research

Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients

Authors: Yongchao Mou, Ghata Nandi, Sukhada Mukte, Eric Chai, Zhenyu Chen, Jorgen E. Nielsen, Troels T. Nielsen, Chiara Criscuolo, Craig Blackstone, Matthew J. Fraidakis, Xue-Jun Li

Published in: Orphanet Journal of Rare Diseases | Issue 1/2023

Login to get access

Abstract

Background

Biallelic mutations in CYP27A1 and CYP7B1, two critical genes regulating cholesterol and bile acid metabolism, cause cerebrotendinous xanthomatosis (CTX) and hereditary spastic paraplegia type 5 (SPG5), respectively. These rare diseases are characterized by progressive degeneration of corticospinal motor neuron axons, yet the underlying pathogenic mechanisms and strategies to mitigate axonal degeneration remain elusive.

Methods

To generate induced pluripotent stem cell (iPSC)-based models for CTX and SPG5, we reprogrammed patient skin fibroblasts into iPSCs by transducing fibroblast cells with episomal vectors containing pluripotency factors. These patient-specific iPSCs, as well as control iPSCs, were differentiated into cortical projection neurons (PNs) and examined for biochemical alterations and disease-related phenotypes.

Results

CTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases. Notably, the bile acid chenodeoxycholic acid (CDCA) effectively mitigated the biochemical alterations and rescued axonal degeneration in patient iPSC-derived neurons. To further examine underlying disease mechanisms, we developed CYP7B1 knockout human embryonic stem cell (hESC) lines using CRISPR-cas9-mediated gene editing and, following differentiation, examined hESC-derived cortical PNs. Knockout of CYP7B1 resulted in similar axonal vesiculation and degeneration in human cortical PN axons, confirming a cause-effect relationship between gene deficiency and axonal degeneration. Interestingly, CYP7B1 deficiency led to impaired neurofilament expression and organization as well as axonal degeneration, which could be rescued with CDCA, establishing a new disease mechanism and therapeutic target to mitigate axonal degeneration.

Conclusions

Our data demonstrate disease-specific lipid disturbances and axonopathy mechanisms in human pluripotent stem cell-based neuronal models of CTX and SPG5 and identify CDCA, an established treatment of CTX, as a potential pharmacotherapy for SPG5. We propose this novel treatment strategy to rescue axonal degeneration in SPG5, a currently incurable condition.
Appendix
Available only for authorised users
Literature
1.
Fester L, Zhou L, Butow A, Huber C, von Lossow R, Prange-Kiel J, et al. Cholesterol-promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampus. Hippocampus. 2009;19(8):692–705.CrossRefPubMed
2.
Goritz C, Mauch DH, Pfrieger FW. Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron. Mol Cell Neurosci. 2005;29(2):190–201.CrossRefPubMed
3.
Abdel-Khalik J, Yutuc E, Crick PJ, Gustafsson JA, Warner M, Roman G, et al. Defective cholesterol metabolism in amyotrophic lateral sclerosis. J Lipid Res. 2017;58(1):267–78.CrossRefPubMed
4.
5.
Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA, Laing NG, et al. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am J Hum Genet. 2008;82(2):510–5.PubMedCentralCrossRefPubMed
6.
7.
Parodi L, Coarelli G, Stevanin G, Brice A, Durr A. Hereditary ataxias and paraparesias: clinical and genetic update. Curr Opin Neurol. 2018;31(4):462–71.CrossRefPubMed
8.
9.
Schule R, Siddique T, Deng HX, Yang Y, Donkervoort S, Hansson M, et al. Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis. J Lipid Res. 2010;51(4):819–23.PubMedCentralCrossRefPubMed
10.
Merino-Serrais P, Loera-Valencia R, Rodriguez-Rodriguez P, Parrado-Fernandez C, Ismail MA, Maioli S, et al. 27-hydroxycholesterol induces aberrant morphology and synaptic dysfunction in hippocampal neurons. Cereb Cortex. 2019;29(1):429–46.CrossRefPubMed
11.
Kim SM, Noh MY, Kim H, Cheon SY, Lee KM, Lee J, et al. 25-Hydroxycholesterol is involved in the pathogenesis of amyotrophic lateral sclerosis. Oncotarget. 2017;8(7):11855–67.PubMedCentralCrossRefPubMed
12.
Wang Y, An Y, Zhang D, Yu H, Zhang X, Tao L, et al. 27-Hydroxycholesterol alters synaptic structural and functional plasticity in hippocampal neuronal cultures. J Neuropathol Exp Neurol. 2019;78(3):238–47.PubMedCentralPubMed
13.
Cali JJ, Hsieh CL, Francke U, Russell DW. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem. 1991;266(12):7779–83.CrossRefPubMed
14.
Salen G, Steiner RD. Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX). J Inherit Metab Dis. 2017;40(6):771–81.CrossRefPubMed
15.
Duell PB, Salen G, Eichler FS, DeBarber AE, Connor SL, Casaday L, et al. Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis. J Clin Lipidol. 2018;12(5):1169–78.CrossRefPubMed
16.
Salen G, Shefer S, Tint GS, Nicolau G, Dayal B, Batta AK. Biosynthesis of bile acids in cerebrotendinous xanthomatosis Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26. J Clin Investig. 1985;76(2):744–51.PubMedCentralCrossRefPubMed
17.
Rickman OJ, Baple EL, Crosby AH. Lipid metabolic pathways converge in motor neuron degenerative diseases. Brain. 2020;143(4):1073–87.CrossRefPubMed
18.
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.CrossRefPubMed
19.
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.CrossRefPubMed
20.
21.
Roos P, Svenstrup K, Danielsen ER, Thomsen C, Nielsen JE. CYP7B1: novel mutations and magnetic resonance spectroscopy abnormalities in hereditary spastic paraplegia type 5A. Acta Neurol Scand. 2014;129(5):330–4.CrossRefPubMed
22.
Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, et al. A more efficient method to generate integration-free human iPS cells. Nat Methods. 2011;8(5):409–12.CrossRefPubMed
23.
Xu CC, Denton KR, Wang ZB, Zhang X, Li XJ. Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy. Dis Model Mech. 2016;9(1):39–49.PubMedCentralPubMed
24.
Boisvert EM, Denton K, Lei L, Li XJ. The specification of telencephalic glutamatergic neurons from human pluripotent stem cells. J Vis Exp. 2013;74:e50321.
25.
Li XJ, Zhang X, Johnson MA, Wang ZB, Lavaute T, Zhang SC. Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development. 2009;136(23):4055–63.PubMedCentralCrossRefPubMed
26.
Zhu PP, Denton KR, Pierson TM, Li XJ, Blackstone C. Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A. Hum Mol Genet. 2014;23(21):5638–48.PubMedCentralCrossRefPubMed
27.
28.
Denton K, Mou Y, Xu CC, Shah D, Chang J, Blackstone C, et al. Impaired mitochondrial dynamics underlie axonal defects in hereditary spastic paraplegias. Hum Mol Genet. 2018;27(14):2517–30.PubMedCentralCrossRefPubMed
29.
Cheng HT, Dauch JR, Porzio MT, Yanik BM, Hsieh W, Smith AG, et al. Increased axonal regeneration and swellings in intraepidermal nerve fibers characterize painful phenotypes of diabetic neuropathy. J Pain. 2013;14(9):941–7.PubMedCentralCrossRefPubMed
30.
Lauria G, Morbin M, Lombardi R, Borgna M, Mazzoleni G, Sghirlanzoni A, et al. Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies. Neurology. 2003;61(5):631–6.CrossRefPubMed
31.
Pop PH, Joosten E, van Spreeken A, Gabreels-Festen A, Jaspar H, ter Laak H, et al. Neuroaxonal pathology of central and peripheral nervous systems in cerebrotendinous xanthomatosis (CTX). Acta Neuropathol. 1984;64(3):259–64.CrossRefPubMed
32.
Voiculescu V, Alexianu M, Popescu-Tismana G, Pastia M, Petrovici A, Dan A. Polyneuropathy with lipid deposits in Schwann cells and axonal degeneration in cerebrotendinous xanthomatosis. J Neurol Sci. 1987;82(1–3):89–99.CrossRefPubMed
33.
Piermarini E, Akarsu S, Connors T, Kneussel M, Lane MA, Morfini G, et al. Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice. Hum Mol Genet. 2022;31(11):1844–59.CrossRefPubMed
34.
Marrone L, Marchi PM, Webster CP, Marroccella R, Coldicott I, Reynolds S, et al. SPG15 protein deficits are at the crossroads between lysosomal abnormalities, altered lipid metabolism and synaptic dysfunction. Hum Mol Genet. 2022;31(16):2693–710.PubMedCentralCrossRefPubMed
35.
De Pace R, Skirzewski M, Damme M, Mattera R, Mercurio J, Foster AM, et al. Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome. PLoS Genet. 2018;14(4): e1007363.PubMedCentralCrossRefPubMed
36.
Fassier C, Tarrade A, Peris L, Courageot S, Mailly P, Dalard C, et al. Microtubule-targeting drugs rescue axonal swellings in cortical neurons from spastin knockout mice. Dis Model Mech. 2013;6(1):72–83.PubMed
37.
Luyckx E, Eyskens F, Simons A, Beckx K, Van West D, Dhar M. Long-term follow-up on the effect of combined therapy of bile acids and statins in the treatment of cerebrotendinous xanthomatosis: a case report. Clin Neurol Neurosurg. 2014;118:9–11.CrossRefPubMed
38.
Verrips A, Wevers RA, Van Engelen BG, Keyser A, Wolthers BG, Barkhof F, et al. Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis. Metabolism. 1999;48(2):233–8.CrossRefPubMed
39.
Rehbach K, Kesavan J, Hauser S, Ritzenhofen S, Jungverdorben J, Schule R, et al. Multiparametric rapid screening of neuronal process pathology for drug target identification in HSP patient-specific neurons. Sci Rep. 2019;9(1):9615.PubMedCentralCrossRefPubMed
40.
Schols L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, et al. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain. 2017;140(12):3112–27.PubMedCentralCrossRefPubMed
41.
Goizet C, Boukhris A, Durr A, Beetz C, Truchetto J, Tesson C, et al. CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain. 2009;132(Pt 6):1589–600.CrossRefPubMed
42.
43.
Denton KR, Lei L, Grenier J, Rodionov V, Blackstone C, Li XJ. Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia. Stem Cells. 2014;32(2):414–23.CrossRefPubMed
44.
Dai D, Mills PB, Footitt E, Gissen P, McClean P, Stahlschmidt J, et al. Liver disease in infancy caused by oxysterol 7 alpha-hydroxylase deficiency: successful treatment with chenodeoxycholic acid. J Inherit Metab Dis. 2014;37(5):851–61.CrossRefPubMed
45.
46.
Bonnot O, Fraidakis MJ, Lucanto R, Chauvin D, Kelley N, Plaza M, et al. Cerebrotendinous xanthomatosis presenting with severe externalized disorder: improvement after one year of treatment with chenodeoxycholic Acid. CNS Spectr. 2010;15(4):231–6.CrossRefPubMed
47.
48.
Voskuhl RR, Itoh N, Tassoni A, Matsukawa MA, Ren E, Tse V, et al. Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis. P Natl Acad Sci USA. 2019;116(20):10130–9.CrossRef
49.
Ismail MA, Mateos L, Maioli S, Merino-Serrais P, Ali Z, Lodeiro M, et al. 27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation. J Exp Med. 2017;214(3):699–717.PubMedCentralCrossRefPubMed
50.
51.
Bramlett KS, Yao S, Burris TP. Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids. Mol Genet Metab. 2000;71(4):609–15.CrossRefPubMed
52.
Kallner M. The effect of chenodeoxycholic acid feeding on bile acid kinetics and fecal neutral steroid excretion in patients with hyperlipoproteinemia types II and IV. J Lab Clin Med. 1975;86(4):595–604.PubMed
53.
Marelli C, Lamari F, Rainteau D, Lafourcade A, Banneau G, Humbert L, et al. Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5. Brain. 2018;141(1):72–84.CrossRefPubMed
54.
Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med. 1984;311(26):1649–52.CrossRefPubMed
55.
Chen Z, Chai E, Mou Y, Roda RH, Blackstone C, Li XJ. Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons. Brain. 2022;145(11):4016–31.CrossRefPubMed
56.
57.
Theofilopoulos S, Griffiths WJ, Crick PJ, Yang S, Meljon A, Ogundare M, et al. Cholestenoic acids regulate motor neuron survival via liver X receptors. J Clin Investig. 2014;124(11):4829–42.PubMedCentralCrossRefPubMed
58.
Yagishita S. Morphological investigations on axonal swellings and spheroids in various human diseases. Virchows Arch A Pathol Anat Histol. 1978;378(3):181–97.CrossRefPubMed
59.
Lang-Ouellette D, Gruver KM, Smith-Dijak A, Blot FGC, Stewart CA, de VanssaydeBlavous P, et al. Purkinje cell axonal swellings enhance action potential fidelity and cerebellar function. Nat Commun. 2021;12(1):4129.PubMedCentralCrossRefPubMed
Metadata
Title
Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients
Authors
Yongchao Mou
Ghata Nandi
Sukhada Mukte
Eric Chai
Zhenyu Chen
Jorgen E. Nielsen
Troels T. Nielsen
Chiara Criscuolo
Craig Blackstone
Matthew J. Fraidakis
Xue-Jun Li
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2023
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-023-02666-w

Other articles of this Issue 1/2023

Orphanet Journal of Rare Diseases 1/2023 Go to the issue

Research

Leigh syndrome global patient registry: uniting patients and researchers worldwide

Review

The use of digital outcome measures in clinical trials in rare neurological diseases: a systematic literature review

Research

PAI1 inhibits the pathogenesis of primary focal hyperhidrosis by targeting CHRNA1

Research

Association between one-session bilateral whole-lung lavage and periprocedural complications in patients with pulmonary alveolar proteinosis: a retrospective cohort study

Research

Prognostic factors for the long term outcome after surgical celiac artery decompression in MALS

Research

A pilot study: handgrip as a predictor in the disease progression of SCA3