ArticleHuman molecular genetics2015
Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 93 citations in OpenAlex.
- Whole-exome sequencing reveals a novel frameshift and a recurrent nonsense SPG11 variant causing rare familial amyotrophic lateral sclerosis type 5 in two consanguineous Pakistani families.Molecular biology reports · 2026Article
- Structural mechanisms of cargo adaptors in membrane trafficking.Current opinion in cell biology · 2026Review
- Maspardin/SPG21 controls lysosome motility and TFEB phosphorylation through RAB7 positioning.The Journal of cell biology · 2026Article
- Structural basis for membrane remodeling by the AP5-SPG11-SPG15 complex.Nature structural & molecular biology · 2025Article
- AP5Z1 affects hepatocellular carcinoma growth and autophagy by regulating PTEN ubiquitination and modulating the PI3K/Akt/mTOR pathway.Journal of translational medicine · 2025Article
- Bi-allelic variants in three genes encoding distinct subunits of the vesicular AP-5 complex cause hereditary macular dystrophy.American journal of human genetics · 2025Article
- Virus infection and vesicle trafficking.Frontiers in immunology · 2025Review
- Endosomal traffic disorders: a driving force behind neurodegenerative diseases.Translational neurodegeneration · 2024Review
- Maternal regulation of the vertebrate oocyte-to-embryo transition.PLoS genetics · 2024Article
- Article
- Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.International journal of molecular sciences · 2024Review
- Movement disorders in hereditary spastic paraplegias.Arquivos de neuro-psiquiatria · 2023Review
- Spatacsin regulates directionality of lysosome trafficking by promoting the degradation of its partner AP5Z1.PLoS biology · 2023Article
- Hereditary spastic paraplegia (SPG 48) with deafness and azoospermia: A case report.Frontiers in neurology · 2023Article
- Protein sorting from endosomes to the TGN.Frontiers in cell and developmental biology · 2023Review
- ESCRT-I fuels lysosomal degradation to restrict TFEB/TFE3 signaling via the Rag-mTORC1 pathway.Life science alliance · 2022Article
- Current Methods to Unravel the Functional Properties of Lysosomal Ion Channels and Transporters.Cells · 2022Review
- The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.Autophagy · 2022Article
- Hereditary Spastic Paraplegia: An Update.International journal of molecular sciences · 2022Review
- Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia.Cells · 2021Review
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Authors and funding
17 authors at 11 institutions in 4 countries.
Funding
Abstract
Adaptor proteins (AP 1-5) are heterotetrameric complexes that facilitate specialized cargo sorting in vesicular-mediated trafficking. Mutations in AP5Z1, encoding a subunit of the AP-5 complex, have been reported to cause hereditary spastic paraplegia (HSP), although their impact at the cellular level has not been assessed. Here we characterize three independent fibroblast lines derived from skin biopsies of patients harbouring nonsense mutations in AP5Z1 and presenting with spastic paraplegia accompanied by neuropathy, parkinsonism and/or cognitive impairment. In all three patient-derived lines, we show that there is complete loss of AP-5 ζ protein and a reduction in the associated AP-5 µ5 protein. Using ultrastructural analysis, we show that these patient-derived lines consistently exhibit abundant multilamellar structures that are positive for markers of endolysosomes and are filled with aberrant storage material organized as exaggerated multilamellar whorls, striated belts and 'fingerprint bodies'. This phenotype can be replicated in a HeLa cell culture model by siRNA knockdown of AP-5 ζ. The cellular phenotype bears striking resemblance to features described in a number of lysosomal storage diseases (LSDs). Collectively, these findings reveal an emerging picture of the role of AP-5 in endosomal and lysosomal homeostasis, illuminates a potential pathomechanism that is relevant to the role of AP-5 in neurons and expands the understanding of recessive HSPs. Moreover, the resulting accumulation of storage material in endolysosomes leads us to propose that AP-5 deficiency represents a new type of LSDs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.