Loss of Ap4s1 in Zebrafish Leads to Neurodevelopmental Defects Resembling Spastic Paraplegia 52

Overview

Journal Ann Clin Transl Neurol

Specialty Neurology

Date 2020 Mar 28

PMID 32216065

Citations 15

Authors

Angelica DAmore

Alessandra Tessa

Valentina Naef

Maria Teresa Bassi

Andrea Citterio

Romina Romaniello

Gianluca Fichi

Daniele Galatolo

Serena Mero

Roberta Battini

Giulia Bertocci

Jacopo Baldacci

Federico Sicca

Federica Gemignani

Ivana Ricca

Anna Rubegni

Jennifer Hirst

Maria Marchese

Mustafa Sahin

Darius Ebrahimi-Fakhari

Filippo M Santorelli

Affiliations

Soon will be listed here.

Abstract

Autosomal recessive spastic paraplegia 52 is caused by biallelic mutations in AP4S1 which encodes a subunit of the adaptor protein complex 4 (AP-4). Using next-generation sequencing, we identified three novel unrelated SPG52 patients from a cohort of patients with cerebral palsy. The discovered variants in AP4S1 lead to reduced AP-4 complex formation in patient-derived fibroblasts. To further understand the role of AP4S1 in neuronal development and homeostasis, we engineered the first zebrafish model of AP-4 deficiency using morpholino-mediated knockdown of ap4s1. In this model, we discovered several phenotypes mimicking SPG52, including altered CNS development, locomotor deficits, and abnormal neuronal excitability.

Citing Articles

Dapagliflozin ameliorates Lafora disease phenotype in a zebrafish model.

Della Vecchia S, Imbrici P, Liantonio A, Naef V, Damiani D, Licitra R Biomed Pharmacother. 2025; 183:117800.

PMID: 39753095 PMC: 11794196. DOI: 10.1016/j.biopha.2024.117800.

An update on autophagy disorders.

Dafsari H, Martinelli D, Saffari A, Ebrahimi-Fakhari D, Fanto M, Dionisi-Vici C J Inherit Metab Dis. 2024; 48(1):e12798.

PMID: 39420677 PMC: 11669743. DOI: 10.1002/jimd.12798.

Diving deep: zebrafish models in motor neuron degeneration research.

Garg V, Geurten B Front Neurosci. 2024; 18:1424025.

PMID: 38966756 PMC: 11222423. DOI: 10.3389/fnins.2024.1424025.

SCAR32: Functional characterization and expansion of the clinical-genetic spectrum.

Naef V, Lieto M, Satolli S, De Micco R, Troisi M, Pasquariello R Ann Clin Transl Neurol. 2024; 11(7):1879-1886.

PMID: 38837640 PMC: 11251466. DOI: 10.1002/acn3.52094.

Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.

Damiani D, Baggiani M, Della Vecchia S, Naef V, Santorelli F Int J Mol Sci. 2024; 25(5).

PMID: 38473862 PMC: 10932093. DOI: 10.3390/ijms25052615.

References

Behne R, Teinert J, Wimmer M, DAmore A, Davies A, Scarrott J . Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking. Hum Mol Genet. 2020; 29(2):320-334. PMC: 7001721. DOI: 10.1093/hmg/ddz310. View

Davies A, Itzhak D, Edgar J, Archuleta T, Hirst J, Jackson L . AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A. Nat Commun. 2018; 9(1):3958. PMC: 6160451. DOI: 10.1038/s41467-018-06172-7. View

Blackstone C . Hereditary spastic paraplegia. Handb Clin Neurol. 2018; 148:633-652. DOI: 10.1016/B978-0-444-64076-5.00041-7. View

Tessa A, Battini R, Rubegni A, Storti E, Marini C, Galatolo D . Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families. Eur J Neurol. 2016; 23(10):1580-7. DOI: 10.1111/ene.13085. View

DAmore A, Tessa A, Casali C, Dotti M, Filla A, Silvestri G . Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study. Front Neurol. 2018; 9:981. PMC: 6289125. DOI: 10.3389/fneur.2018.00981. View

Abou Jamra R, Philippe O, Raas-Rothschild A, Eck S, Graf E, Buchert R . Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet. 2011; 88(6):788-795. PMC: 3113253. DOI: 10.1016/j.ajhg.2011.04.019. View

Fassier C, Hutt J, Scholpp S, Lumsden A, Giros B, Nothias F . Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway. Nat Neurosci. 2010; 13(11):1380-7. DOI: 10.1038/nn.2662. View

Kircher M, Witten D, Jain P, ORoak B, Cooper G, Shendure J . A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014; 46(3):310-5. PMC: 3992975. DOI: 10.1038/ng.2892. View

Peng S, Yao L, Cui C, Zhao H, Liu C, Li Y . Semaphorin4D promotes axon regrowth and swimming ability during recovery following zebrafish spinal cord injury. Neuroscience. 2017; 351:36-46. DOI: 10.1016/j.neuroscience.2017.03.030. View

10.

Vill K, Muller-Felber W, Alhaddad B, Strom T, Teusch V, Weigand H . A homozygous splice variant in AP4S1 mimicking neurodegeneration with brain iron accumulation. Mov Disord. 2017; 32(5):797-799. DOI: 10.1002/mds.26922. View

11.

Hardies K, May P, Djemie T, Tarta-Arsene O, Deconinck T, Craiu D . Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. Hum Mol Genet. 2015; 24(8):2218-27. PMC: 4380070. DOI: 10.1093/hmg/ddu740. View

12.

Teinert J, Behne R, DAmore A, Wimmer M, Dwyer S, Chen T . Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4B1-associated hereditary spastic paraplegia (SPG47). Stem Cell Res. 2019; 40:101575. PMC: 7269118. DOI: 10.1016/j.scr.2019.101575. View

13.

Ivankovic D, Drew J, Lesept F, White I, Lopez Domenech G, Tooze S . Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome. Autophagy. 2019; 16(3):391-407. PMC: 6999640. DOI: 10.1080/15548627.2019.1615302. View

14.

Carmona S, Marecos C, Amorim M, Ferreira A, Conceicao C, Bras J . splice-site mutation in a case of spastic paraplegia type 52 with polymicrogyria. Neurol Genet. 2018; 4(5):e273. PMC: 6167175. DOI: 10.1212/NXG.0000000000000273. View

15.

De Pace R, Skirzewski M, Damme M, Mattera R, Mercurio J, Foster A . 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. PMC: 5940238. DOI: 10.1371/journal.pgen.1007363. View

16.

Butler R, Wood J, Landers J, Cunliffe V . Genetic and chemical modulation of spastin-dependent axon outgrowth in zebrafish embryos indicates a role for impaired microtubule dynamics in hereditary spastic paraplegia. Dis Model Mech. 2010; 3(11-12):743-51. PMC: 2965401. DOI: 10.1242/dmm.004002. View

17.

Southgate L, Dafou D, Hoyle J, Li N, Kinning E, Critchley P . Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish. Neurogenetics. 2010; 11(4):379-89. PMC: 2944959. DOI: 10.1007/s10048-010-0243-8. View

18.

Marchese M, Pappalardo A, Baldacci J, Verri T, Doccini S, Cassandrini D . Dolichol-phosphate mannose synthase depletion in zebrafish leads to dystrophic muscle with hypoglycosylated α-dystroglycan. Biochem Biophys Res Commun. 2016; 477(1):137-143. DOI: 10.1016/j.bbrc.2016.06.033. View