Decoding hereditary spastic paraplegia pathogenicity through transcriptomic profiling

Nicolas James Ho; Xiao Chen; Yong Lei; Shen Gu

doi:10.24272/j.issn.2095-8137.2022.281

Volume 44 Issue 3

May 2023

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Nicolas James Ho, Xiao Chen, Yong Lei, Shen Gu. Decoding hereditary spastic paraplegia pathogenicity through transcriptomic profiling. Zoological Research, 2023, 44(3): 650-662. doi: 10.24272/j.issn.2095-8137.2022.281

Citation:

Nicolas James Ho, Xiao Chen, Yong Lei, Shen Gu. Decoding hereditary spastic paraplegia pathogenicity through transcriptomic profiling. Zoological Research, 2023, 44(3): 650-662. doi: 10.24272/j.issn.2095-8137.2022.281

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Decoding hereditary spastic paraplegia pathogenicity through transcriptomic profiling

doi: 10.24272/j.issn.2095-8137.2022.281

Nicolas James Ho¹,
Xiao Chen^{2, 3, 4, 5, 6},
Yong Lei^{7, 8
,
,},
Shen Gu^{1, 9, 10, 11
,
,}

1.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
2.
Dr. Li Dak Sum-Yip Yio Chin Center for Stem Cells and Regenerative Medicine and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
3.
Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
4.
Zhejiang University-University of Edinburgh Institute & School of Basic Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
5.
Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
6.
China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, Zhejiang, 310058 China
7.
School of Medicine, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong 518172, China
8.
The Chinese University of Hong Kong (Shenzhen), Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong 518172, China
9.
Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
10.
Kunming Institute of Zoology - The Chinese University of Hong Kong (KIZ-CUHK) Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Hong Kong SAR, China
11.
Hong Kong Branch of CAS Center for Excellence in Animal Evolution and Genetics, The Chinese University of Hong Kong, Hong Kong SAR, China

The HSP genes used in this study are available via the OMIM PS303350 phenotypic series (https://omim.org/phenotypicSeries/PS303350) (last accessed on 14 September 2021). The tissue-specific transcriptomic datasets analyzed in this study are available via the v20 Human Protein Atlas portal (https://v20.proteinatlas.org/) (last accessed on 14 November 2021). The expression data with developmental time are accessible via the EMBL-EBI Expression Atlas portal (https://www.ebi.ac.uk/gxa/home) (last accessed on 11 December 2021). The scRNA-seq datasets are available from the Allen Institute cell-type database (RNA-Seq Data) (https://portal.brain-map.org/atlases-and-data/rnaseq) (last accessed on 28 December 2021). The mouse motor cortical Patch-seq dataset is available at GitHub (https://github.com/berenslab/mini-atlas) (last accessed on 9 June 2022). The cross-species snRNA-seq dataset is available via Cytosplore Viewer (https://viewer.cytosplore.org/) (last accessed on 10 June 2022). The pLI scores are available from the gnomAD browser (https://gnomad.broadinstitute.org/) (last accessed on 20 May 2022). The CFG scores of HSP genes are available from the AlzData database (http://alzdata.org/) (last accessed on 24 November 2022).
Supplementary data to this article can be found online.
The authors declare that they have no competing interests.
N.J.H. acquired, analyzed, and interpreted the data. N.J.H. and S.G. designed the study and wrote the manuscript. X.C. and Y.L. conceived, critically revised, and supervised the work. All authors read and approved the final version of the manuscript.

Funds: This study was supported by the General Research Fund from the Research Grants Council of Hong Kong (24101921), Direct Grant from the Chinese University of Hong Kong (2020.096), National Natural Science Foundation of China (32170583, 82202045), Hong Kong RGC-CRF Equipment Fund C5033-19E, Shenzhen-Hong Kong Cooperation Zone for Technology and Innovation (HZQB-KCZYB-2020056), and Ganghong Young Scholar Development Fund (to Y.L.). Additional support was provided by the Hong Kong Branch of the CAS Center for Excellence in Animal Evolution and Genetics, Chinese University of Hong Kong (8601010)

More Information

Corresponding author: E-mail: leiyong@cuhk.edu.cn; shengu@cuhk.edu.hk
Received Date: 2022-12-30
Accepted Date: 2023-05-10

Published Online: 2023-05-10

Publish Date: 2023-05-18

Abstract

Abstract

Hereditary spastic paraplegia (HSP) is a group of genetic motor neuron diseases resulting from length-dependent axonal degeneration of the corticospinal upper motor neurons. Due to the advancement of next-generation sequencing, more than 70 novel HSP disease-causing genes have been identified in the past decade. Despite this, our understanding of HSP physiopathology and the development of efficient management and treatment strategies remain poor. One major challenge in studying HSP pathogenicity is selective neuronal vulnerability, characterized by the manifestation of clinical symptoms that are restricted to specific neuronal populations, despite the presence of germline disease-causing variants in every cell of the patient. Furthermore, disease genes may exhibit ubiquitous expression patterns and involve a myriad of different pathways to cause motor neuron degeneration. In the current review, we explore the correlation between transcriptomic data and clinical manifestations, as well as the importance of interspecies models by comparing tissue-specific transcriptomic profiles of humans and mice, expression patterns of different genes in the brain during development, and single-cell transcriptomic data from related tissues. Furthermore, we discuss the potential of emerging single-cell RNA sequencing technologies to resolve unanswered questions related to HSP pathogenicity.
- Hereditary spastic paraplegia,
- Motor neuron degeneration,
- Disease pathogenicity,
- Transcriptome analysis,
- Single-cell RNA sequencing

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References(86)

References

[1]	Abdollahpour H, Alawi M, Kortum F, et al. 2015. An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome. European Journal of Human Genetics, 23(2): 256−259. doi: 10.1038/ejhg.2014.73
[2]	Al-Saif A, Bohlega S, Al-Mohanna F. 2012. Loss of ERLIN2 function leads to juvenile primary lateral sclerosis. Annals of Neurology, 72(4): 510−516. doi: 10.1002/ana.23641
[3]	Allen Institute. 2021. Cell types database: RNA-Seq data.https://portal.brain-map.org/atlases-and-data/rnaseq.
[4]	Bakken TE, Jorstad NL, Hu QW, et al. 2021. Comparative cellular analysis of motor cortex in human, marmoset and mouse. Nature, 598(7879): 111−119. doi: 10.1038/s41586-021-03465-8
[5]	Beetz C, Koch N, Khundadze M, et al. 2013. A spastic paraplegia mouse model reveals REEP1-dependent ER shaping. The Journal of Clinical Investigation, 123(10): 4273−4282. doi: 10.1172/JCI65665
[6]	Bellofatto M, De Michele G, Iovino A, et al. 2019. Management of hereditary spastic paraplegia: a systematic review of the literature. Frontiers in Neurology, 10: 3. doi: 10.3389/fneur.2019.00003
[7]	Bross P, Fernandez-Guerra P. 2016. Disease-associated mutations in the HSPD1 gene encoding the large subunit of the mitochondrial HSP60/HSP10 chaperonin complex. Frontiers in Molecular Biosciences, 3: 49.
[8]	Cardoso-Moreira M, Halbert J, Valloton D, et al. 2019. Gene expression across mammalian organ development. Nature, 571(7766): 505−509. doi: 10.1038/s41586-019-1338-5
[9]	Charvin D, Cifuentes-Diaz C, Fonknechten N, et al. 2003. Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus. Human Molecular Genetics, 12(1): 71−78. doi: 10.1093/hmg/ddg004
[10]	Cheon CK, Lim SH, Kim YM, et al. 2017. Autosomal dominant transmission of complicated hereditary spastic paraplegia due to a dominant negative mutation of KIF1A, SPG30 gene. Scientific Reports, 7(1): 12527. doi: 10.1038/s41598-017-12999-9
[11]	Clemen CS, Schmidt A, Winter L, et al. 2022. N471D WASH complex subunit strumpellin knock-in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue. Neuropathology and Applied Neurobiology, 48(1): e12750.
[12]	Cohen M, Giladi A, Raposo C, et al. 2021. Meningeal lymphoid structures are activated under acute and chronic spinal cord pathologies. Life Science Alliance, 4(1): e202000907. doi: 10.26508/lsa.202000907
[13]	Cömert C, Brick L, Ang D, et al. 2020. A recurrent de novo HSPD1 variant is associated with hypomyelinating leukodystrophy. Cold Spring Harbor Molecular Case Studies, 6(3): a004879. doi: 10.1101/mcs.a004879
[14]	Coutelier M, Goizet C, Durr A, et al. 2015. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain, 138(Pt 8): 2191–2205.
[15]	De Souza PVS, De Rezende Pinto WBV, De Rezende Batistella GN, et al. 2017. Hereditary spastic paraplegia: clinical and genetic hallmarks. The Cerebellum, 16(2): 525−551. doi: 10.1007/s12311-016-0803-z
[16]	DeLuca GC, Ebers GC, Esiri MM. 2004. The extent of axonal loss in the long tracts in hereditary spastic paraplegia. Neuropathology and Applied Neurobiology, 30(6): 576−584. doi: 10.1111/j.1365-2990.2004.00587.x
[17]	Deng HF, Xiao X, Yang T, et al. 2021. A genetically defined insula-brainstem circuit selectively controls motivational vigor. Cell, 184(26): 6344−6360.e18. doi: 10.1016/j.cell.2021.11.019
[18]	Deschauer M, Gaul C, Behrmann C, et al. 2012. C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis. Journal of Neurology, 259(11): 2434−2439. doi: 10.1007/s00415-012-6521-7
[19]	Enjyoji K, Sévigny J, Lin Y, et al. 1999. Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nature Medicine, 5(9): 1010−1017. doi: 10.1038/12447
[20]	Errico A, Ballabio A, Rugarli EI. 2002. Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Human Molecular Genetics, 11(2): 153−163. doi: 10.1093/hmg/11.2.153
[21]	Fard MAF, Rebelo AP, Buglo E, et al. 2019. Truncating mutations in UBAP1 cause hereditary spastic paraplegia. The American Journal of Human Genetics, 104(6): 1251. doi: 10.1016/j.ajhg.2019.05.009
[22]	Friedman DJ, Rennke HG, Csizmadia E, et al. 2007. The vascular ectonucleotidase ENTPD1 is a novel renoprotective factor in diabetic nephropathy. Diabetes, 56(9): 2371−2379. doi: 10.2337/db06-1593
[23]	Füger P, Sreekumar V, Schule R, et al. 2012. Spastic paraplegia mutation N256S in the neuronal microtubule motor KIF5A disrupts axonal transport in a Drosophila HSP model. PLoS Genetics, 8(11): e1003066. doi: 10.1371/journal.pgen.1003066
[24]	Gan-Or Z, Bouslam N, Birouk N, et al. 2016. Mutations in CAPN1 cause autosomal-recessive hereditary spastic paraplegia. The American Journal of Human Genetics, 98(5): 1038−1046. doi: 10.1016/j.ajhg.2016.04.002
[25]	Gareis FJ, Mason JD, Opitz JM. 1984. X-linked mental retardation associated with bilateral clasp thumb anomaly. American Journal of Medical Genetics, 17(1): 333−338. doi: 10.1002/ajmg.1320170126
[26]	Genc B, Gozutok O, Ozdinler PH. 2019. Complexity of generating mouse models to study the upper motor neurons: let us shift focus from mice to neurons. International Journal of Molecular Sciences, 20(16): 3848. doi: 10.3390/ijms20163848
[27]	Goytain A, Hines RM, El-Husseini A, et al. 2007. NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg²⁺ transporter. The Journal of Biological Chemistry, 282(11): 8060−8068. doi: 10.1074/jbc.M610314200
[28]	Gregory JM, McDade K, Livesey MR, et al. 2020. Spatial transcriptomics identifies spatially dysregulated expression of GRM3 and USP47 in amyotrophic lateral sclerosis. Neuropathology and Applied Neurobiology, 46(5): 441−457. doi: 10.1111/nan.12597
[29]	Gu S, Chen CA, Rosenfeld JA, et al. 2020. Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia. Human Mutation, 41(3): 632−640. doi: 10.1002/humu.23950
[30]	Gumeni S, Vantaggiato C, Montopoli M, et al. 2021. Hereditary spastic paraplegia and future therapeutic directions: beneficial effects of small compounds acting on cellular stress. Frontiers in Neuroscience, 15: 660714. doi: 10.3389/fnins.2021.660714
[31]	Hedera P. 1993. Hereditary spastic paraplegia overview. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al. GeneReviews^®. Seattle: University of Washington.
[32]	Heimer G, Oz-Levi D, Eyal E, et al. 2016. TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability. European Journal of Paediatric Neurology, 20(1): 69−79. doi: 10.1016/j.ejpn.2015.10.003
[33]	Ho R, Workman MJ, Mathkar P, et al. 2021. Cross-comparison of human iPSC motor neuron models of familial and sporadic ALS reveals early and convergent transcriptomic disease signatures. Cell Systems, 12(2): 159−175.e9. doi: 10.1016/j.cels.2020.10.010
[34]	Hwang B, Lee JH, Bang D. 2018. Single-cell RNA sequencing technologies and bioinformatics pipelines. Experimental & Molecular Medicine, 50(8): 1−14.
[35]	Ito D, Suzuki N. 2007. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Annals of Neurology, 61(3): 237−250. doi: 10.1002/ana.21070
[36]	Jahic A, Khundadze M, Jaenisch N, et al. 2015. The spectrum of KIAA0196 variants, and characterization of a murine knockout: implications for the mutational mechanism in hereditary spastic paraplegia type SPG8. Orphanet Journal of Rare Diseases, 10: 147. doi: 10.1186/s13023-015-0359-x
[37]	Jamra RA, Philippe O, Raas-Rothschild A, et al. 2011. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. The American Journal of Human Genetics, 88(6): 788−795. doi: 10.1016/j.ajhg.2011.04.019
[38]	Kaepernick L, Legius E, Higgins J, et al. 1994. Clinical aspects of the MASA syndrome in a large family, including expressing females. Clinical Genetics, 45(4): 181−185.
[39]	Karczewski KJ, Francioli LC, Tiao G, et al. 2020. The mutational constraint spectrum quantified from variation in 141, 456 humans. Nature, 581(7809): 434−443. doi: 10.1038/s41586-020-2308-7
[40]	Klebe S, Stevanin G, Depienne C. 2015. Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting. Revue Neurologique, 171(6–7): 505–530.
[41]	Komachali SR, Sheikholeslami M, Salehi M. 2022. A novel mutation in GJC2 associated with hypomyelinating leukodystrophy type 2 disorder. Genomics & Informatics, 20(2): e24.
[42]	Kruer MC, Paudel R, Wagoner W, et al. 2012. Analysis of ATP13A2 in large neurodegeneration with brain iron accumulation (NBIA) and dystonia-parkinsonism cohorts. Neuroscience Letters, 523(1): 35−38. doi: 10.1016/j.neulet.2012.06.036
[43]	Lemon RN. 2008. Descending pathways in motor control. Annual Review of Neuroscience, 31: 195−218. doi: 10.1146/annurev.neuro.31.060407.125547
[44]	Li ML, Wu SH, Zhang JJ, et al. 2019. 547 transcriptomes from 44 brain areas reveal features of the aging brain in non-human primates. Genome Biology, 20(1): 258. doi: 10.1186/s13059-019-1866-1
[45]	Liu WT, Venugopal S, Majid S, et al. 2020. Single-cell RNA-seq analysis of the brainstem of mutant SOD1 mice reveals perturbed cell types and pathways of amyotrophic lateral sclerosis. Neurobiology of Disease, 141: 104877. doi: 10.1016/j.nbd.2020.104877
[46]	Loomba S, Straehle J, Gangadharan V, et al. 2022. Connectomic comparison of mouse and human cortex. Science, 377(6602): eabo0924. doi: 10.1126/science.abo0924
[47]	Lossos A, Elazar N, Lerer I, et al. 2015. Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder. Brain, 138(Pt 9): 2521–2536.
[48]	MacLean M, López-Díez R, Vasquez C, et al. 2022. Neuronal-glial communication perturbations in murine SOD1^G93A spinal cord. Communications Biology, 5(1): 177. doi: 10.1038/s42003-022-03128-y
[49]	Mannan AU, Krawen P, Sauter SM, et al. 2006. ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia. The American Journal of Human Genetics, 79(2): 351−357. doi: 10.1086/504927
[50]	Mao F, Li ZH, Zhao BY, et al. 2015. Identification and functional analysis of a SLC33A1: c. 339T>G (p. Ser113Arg) variant in the original SPG42 family. Human Mutation, 36(2): 240−249. doi: 10.1002/humu.22732
[51]	Matsumoto N, Watanabe N, Iibe N, et al. 2019. Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation. Biochemistry and Biophysics Reports, 20: 100705. doi: 10.1016/j.bbrep.2019.100705
[52]	Meijer IA, Dion P, Laurent S, et al. 2007. Characterization of a novel SPG3A deletion in a French-Canadian family. Annals of Neurology, 61(6): 599−603. doi: 10.1002/ana.21114
[53]	Mifflin L, Hu ZR, Dufort C, et al. 2021. A RIPK1-regulated inflammatory microglial state in amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 118(13): e2025102118. doi: 10.1073/pnas.2025102118
[54]	Montecchiani C, Pedace L, Lo Giudice T, et al. 2016. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain, 139(Pt 1): 73–85.
[55]	Montenegro G, Rebelo AP, Connell J, et al. 2012. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. The Journal of Clinical Investigation, 122(2): 538−544. doi: 10.1172/JCI60560
[56]	Muglia M, Magariello A, Nicoletti G, et al. 2002. Further evidence that SPG3A gene mutations cause autosomal dominant hereditary spastic paraplegia. Annals of Neurology, 51(6): 794−795.
[57]	Namboori SC, Thomas P, Ames R, et al. 2021. Single-cell transcriptomics identifies master regulators of neurodegeneration in SOD1 ALS iPSC-derived motor neurons. Stem Cell Reports, 16(12): 3020−3035. doi: 10.1016/j.stemcr.2021.10.010
[58]	Neuser S, Brechmann B, Heimer G, et al. 2021. Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability. Human Mutation, 42(6): 762−776. doi: 10.1002/humu.24206
[59]	Online Mendelian Inheritance in Man. 2021. OMIM Phenotypic Series - PS303350. in Spastic paraplegia - PS303350. Vol. 2021. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD).
[60]	Orphanet Rare Disease Portal. 2021. Orphanet rare disease portal. Vol. 2021.
[61]	Orso G, Martinuzzi A, Rossetto MG, et al. 2005. Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. Journal of Clinical Investigation, 115(11): 3026−3034. doi: 10.1172/JCI24694
[62]	Orthmann-Murphy JL, Salsano E, Abrams CK, et al. 2009. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain, 132(Pt 2): 426–438.
[63]	Orvis J, Gottfried B, Kancherla J, et al. 2021. gEAR: Gene Expression Analysis Resource portal for community-driven, multi-omic data exploration. Nature Methods, 18(8): 843−844. doi: 10.1038/s41592-021-01200-9
[64]	Panza E, Escamilla-Honrubia JM, Marco-Marín C, et al. 2016. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism. Brain, 139(Pt 1): e3.
[65]	Pujol C, Legrand A, Parodi L, et al. 2021. Implication of folate deficiency in CYP2U1 loss of function. Journal of Experimental Medicine, 218(11): e20210846. doi: 10.1084/jem.20210846
[66]	Robinson MD, Oshlack A. 2010. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biology, 11(3): R25. doi: 10.1186/gb-2010-11-3-r25
[67]	Ruano L, Melo C, Silva MC, et al. 2014. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology, 42(3): 174−183. doi: 10.1159/000358801
[68]	Saez-Atienzar S, Bandres-Ciga S, Langston RG, et al. 2021. Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types. Science Advances, 7(3): eabd9036. doi: 10.1126/sciadv.abd9036
[69]	Scala F, Kobak D, Bernabucci M, et al. 2021. Phenotypic variation of transcriptomic cell types in mouse motor cortex. Nature, 598(7879): 144−150. doi: 10.1038/s41586-020-2907-3
[70]	Ségalat L. 2007. Loss-of-function genetic diseases and the concept of pharmaceutical targets. Orphanet Journal of Rare Diseases, 2: 30. doi: 10.1186/1750-1172-2-30
[71]	Song L, Rijal R, Karow M, et al. 2018. Expression of N471D strumpellin leads to defects in the endolysosomal system. Disease Models & Mechanisms, 11(9): dmm033449.
[72]	Szebényi K, Wenger LMD, Sun Y, et al. 2021. Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology. Nature Neuroscience, 24(11): 1542−1554. doi: 10.1038/s41593-021-00923-4
[73]	Tesson C, Nawara M, Salih MAM, et al. 2012. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. The American Journal of Human Genetics, 91(6): 1051−1064. doi: 10.1016/j.ajhg.2012.11.001
[74]	Tsai PC, Huang YH, Guo YC, et al. 2014. A novel TFG mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function. Neurology, 83(10): 903−912. doi: 10.1212/WNL.0000000000000758
[75]	Tüysüz B, Bilguvar K, Koçer N, et al. 2014. Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. American Journal of Medical Genetics Part A, 164(7): 1677−1685. doi: 10.1002/ajmg.a.36514
[76]	Uhlen M, Fagerberg L, Hallström BM, et al. 2015. Tissue-based map of the human proteome. Science, 347(6220): e1260419. doi: 10.1126/science.1260419
[77]	Van Den Berg RA, Hoefsloot HCJ, Westerhuis JA, et al. 2006. Centering, scaling, and transformations: improving the biological information content of metabolomics data. BMC Genomics, 7: 142. doi: 10.1186/1471-2164-7-142
[78]	Vandamme TF. 2014. Use of rodents as models of human diseases. Journal of Pharmacy & BioAllied Sciences, 6(1): 2−9.
[79]	Vaz FM, McDermott JH, Alders M, et al. 2019. Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia. Brain, 142(11): 3382−3397. doi: 10.1093/brain/awz291
[80]	Veitia RA, Caburet S, Birchler JA. 2018. Mechanisms of Mendelian dominance. Clinical Genetics, 93(3): 419−428. doi: 10.1111/cge.13107
[81]	Walusinski O. 2020. A historical approach to hereditary spastic paraplegia. Revue Neurologique, 176(4): 225−234. doi: 10.1016/j.neurol.2019.11.003
[82]	Winter RM, Davies KE, Bell MV, et al. 1989. MASA syndrome: further clinical delineation and chromosomal localisation. Human Genetics, 82(4): 367−370.
[83]	Xu M, Zhang DF, Luo RC, et al. 2018. A systematic integrated analysis of brain expression profiles reveals YAP1 and other prioritized hub genes as important upstream regulators in Alzheimer's disease. Alzheimer’s & Dementia, 14(2): 215−229.
[84]	Yao ZZ, Van Velthoven CTJ, Nguyen TN, et al. 2021. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell, 184(12): 3222−3241.e26. doi: 10.1016/j.cell.2021.04.021
[85]	Yıldırım Y, Orhan EK, Iseri SAU, et al. 2011. A frameshift mutation of ERLIN2 in recessive intellectual disability, motor dysfunction and multiple joint contractures. Human Molecular Genetics, 20(10): 1886−1892. doi: 10.1093/hmg/ddr070
[86]	Yim AKY, Wang PL, Bermingham JR et al. 2022. Disentangling glial diversity in peripheral nerves at single-nuclei resolution. Nature Neuroscience, 25(2): 238−251. doi: 10.1038/s41593-021-01005-1