AP-4 deficiency underlies four types of HSP
AP-4 deficiency is associated with SPG 47, 50, 51 and 52 types of HSP. This study identified a particular protein, ATG9A, the distribution of which is significantly altered in both mice and people with these types of HSPs.
The hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of disorders characterized by progressive lower limb spasticity. Mutations in subunits of the heterotetrameric (ε-β4-μ4-σ4) adaptor protein 4 (AP-4) complex cause an autosomal recessive form of complicated HSP referred to as “AP-4 deficiency syndrome”. In addition to lower limb spasticity, this syndrome features intellectual disability, microcephaly, seizures, thin corpus callosum and upper limb spasticity. The pathogenetic mechanism, however, remains poorly understood.
Here we report the characterization of a knockout (KO) mouse for the AP4E1 gene encoding the ε subunit of AP-4. We find that AP-4 ε KO mice exhibit a range of neurological phenotypes, including hindlimb clasping, decreased motor coordination and weak grip strength. In addition, AP-4 ε KO mice display a thin corpus callosum and axonal swellings in various areas of the brain and spinal cord.
Immunohistochemical analyses show that the transmembrane autophagy-related protein 9A (ATG9A) is more concentrated in the trans-Golgi network (TGN) and depleted from the peripheral cytoplasm both in skin fibroblasts from patients with mutations in the μ4 subunit of AP-4 and in various neuronal types in AP-4 ε KO mice. ATG9A mislocalization is associated with increased tendency to accumulate mutant huntingtin (HTT) aggregates in the axons of AP-4 ε KO neurons.
These findings indicate that the AP-4 ε KO mouse is a suitable animal model for AP-4 deficiency syndrome, and that defective mobilization of ATG9A from the TGN and impaired autophagic degradation of protein aggregates might contribute to neuroaxonal dystrophy in this disorder.
SOURCE: PLoS Genet. 2018 Apr 26;14(4):e1007363. doi: 10.1371/journal.pgen.1007363. eCollection 2018 Apr. PMID: 29698489
Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome.
1 Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
2 Section of Molecular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
3 Institute of Biochemistry, Christian-Albrechts University of Kiel, Kiel, Germany.
4 Division of Veterinary Resources, National Institutes of Health, Bethesda, Maryland, United States of America.
5 NIH Mouse Imaging Facility/NIH Magnetic Resonance Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
6 Laboratory of Communication Disorders, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States of America.
7 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.