Adaptor Protein (AP) genes linked with 5 types of HSP

Mechanisms & processes described in 3 research studies


There are two Adaptor Protein complexes, AP-4 (with 4 sub-units) and AP-5, where mutations of the genes involved are associated with five different types of HSP … AP-4 with SPG47, 50, 51 and 52; and AP-5 with SPG48 … all with diverse symptom profiles.


Whilst these are all complicated forms of HSP, and the AP all exhibit abnormalities of organelle and cell membrane function in neurons, different pathways at the cell and molecular level are described in these studies.



This first study of SPG47 HSP expands the known mode of inheritance to include compound heterozygous mutations with parents who are not blood-relatives. The four different genes associated with SPG47, SPG50, SPG51 and SPG52 types of HSP all have variants causing forms of cerebral palsy.


The study identifies overlap between some of the features of AP-4 deficiency with those of cerebral palsy and together with the new finding of unrelated parents leads to the conclusion that AP-4 deficiency may be more common than previously thought.



The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity.


One subtype, spastic paraplegia type 47 (SPG47 or HSP-AP4B1), is due to bi-allelic loss-of-function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP-4), a heterotetrameric protein complex that regulates the transport of membrane proteins.


Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1-associated SPG47, the majority born to non-consanguineous parents and carrying compound heterozygous mutations.


Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss.


Given that some of the features of AP-4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non-consanguineous populations, we believe that AP-4 deficiency may be more common than previously appreciated.


SOURCE: Am J Med Genet A. 2018 Feb;176(2):311-318. doi: 10.1002/ajmg.a.38561. Epub 2017 Nov 28. PMID: 29193663


Clinical and genetic characterization of AP4B1-associated SPG47.


Ebrahimi-Fakhari D1,2, Cheng C3, Dies K1, Diplock A1, Pier DB1,4, Ryan CS5, Lanpher BC6, Hirst J7, Chung WK8, Sahin M1, Rosser E9, Darras B1, Bennett JT10; CureSPG47.

1 Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts.

2 Division of General Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts.

3 Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington.

4 Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.

5 Department of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota.

6 Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota.

7 Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK.

8 Department of Pediatrics and Medicine, Columbia University Medical Center, New York, New York.

9 Department of Clinical Genetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

10 Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, and Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.



The Adaptor Protein (AP-4) complex family is revealed in this second study as a regulator of the waste and foreign matter collection and disposal machinery within cells, which occurs in structures called autophagosomes. These structures and the systems they employ are thought to be defective in cells with these mutations.



© J Cell Sci 2015 128: 185-192; doi: 10.1242/jcs.158758


AP-4 is a member of the heterotetrameric adaptor protein (AP) complex family involved in protein sorting in the endomembrane system of eukaryotic cells. Interest in AP-4 has recently risen with the discovery that mutations in any of its four subunits cause a form of hereditary spastic paraplegia (HSP) with intellectual disability.


The critical sorting events mediated by AP-4 and the pathogenesis of AP-4 deficiency, however, remain poorly understood. Here we report the identification of ATG9A, the only multispanning membrane component of the core autophagy machinery, as a specific AP-4 cargo. AP-4 promotes signal-mediated export of ATG9A from the trans-Golgi network to the peripheral cytoplasm, contributing to lipidation of the autophagy protein LC3B and maturation of preautophagosomal structures. These findings implicate AP-4 as a regulator of autophagy and altered autophagy as a possible defect in AP-4-deficient HSP.


SOURCE: Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):E10697-E10706. doi: 10.1073/pnas.1717327114. Epub 2017 Nov 27. PMID: 29180427 PMCID: PMC5740629 [Available on 2018-06-12]


AP-4 mediates export of ATG9A from the trans-Golgi network to promote autophagosome formation.


Mattera R1, Park SY1, De Pace R1, Guardia CM1, Bonifacino JS2.

1 Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.

2 Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 [email protected].



Mutations in the Adaptor Protein (AP-5) complex, causing SPG48 type HSP, are associated with buildup of impaired lysosomes in cells. This study sheds light on the cellular pathways and the cargoes involved and describes the connections and interactions with other proteins and organelles in a description of the mechanisms and processes responsible.

© BioEssays 36(6) June 2014


The AP-5 adaptor protein complex is presumed to function in membrane traffic, but so far nothing is known about its pathway or its cargo. We have used CRISPR-Cas9 to knock out the AP-5 ζ subunit gene, AP5Z1, in HeLa cells, and then analysed the phenotype by subcellular fractionation profiling and quantitative mass spectrometry. The retromer complex had an altered steady-state distribution in the knockout cells, and several Golgi proteins, including GOLIM4 and GOLM1, were depleted from vesicle-enriched fractions.


Immunolocalisation showed that loss of AP-5 led to impaired retrieval of the cation-independent mannose 6-phosphate receptor (CIMPR), GOLIM4, and GOLM1 from endosomes back to the Golgi region. Knocking down the retromer complex exacerbated this phenotype. Both the CIMPR and sortilin interacted with the AP-5-associated protein SPG15 in pull-down assays, and we propose that sortilin may act as a link between Golgi proteins and the AP-5/SPG11/SPG15 complex.


Together, our findings suggest that AP-5 functions in a novel sorting step out of late endosomes, acting as a backup pathway for retromer. This provides a mechanistic explanation for why mutations in AP-5/SPG11/SPG15 cause cells to accumulate aberrant endolysosomes, and highlights the role of endosome/lysosome dysfunction in the pathology of hereditary spastic paraplegia and other neurodegenerative disorders.


SOURCE: PLoS Biol. 2018 Jan 30;16(1):e2004411. doi: 10.1371/journal.pbio.2004411. eCollection 2018 Jan. PMID: 29381698


Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval.


Hirst J1, Itzhak DN2, Antrobus R1, Borner GHH2, Robinson MS1.


1 University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom.

2 Max-Planck Institute of Biochemistry, Martinsried, Germany.


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