Journal Article

Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome

Hoffmann, Victoria, Bonifacino, Juan S., Jarnik, Michal, Damme, Markus, Skirzewski, Miguel, Foster, Arianne M., De Pace, Raffaella, Han, Tae-Un, Mercurio, Jeffrey, Buonanno, Andrés, Morris, H. Douglas, Mattera, Rafael, Cuitino, Loreto, Mancini, Grazia M. S.

2018

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptor Protein Complex 4 - chemistry / Adaptor Protein Complex 4 - deficiency / Adaptor Protein Complex 4 - genetics / Adaptor Protein Complex Subunits - chemistry / Adaptor Protein Complex Subunits - deficiency / Adaptor Protein Complex Subunits - genetics / Animals / Autophagy / Autophagy-Related Proteins - metabolism / Axons / Axons - metabolism / Behavior, Animal - physiology / Biology / Biology and Life Sciences / Brain - metabolism / Brain - pathology / Cell death / Childrens health / Corpus callosum / Cytoplasm / Development and progression / Diagnosis / Disease Models, Animal / Dystrophy / Female / Fibroblasts / Funding / Genes / Genetic aspects / Golgi apparatus / Humans / Huntingtin / Huntingtin Protein - chemistry / Huntingtin Protein - genetics / Huntingtin Protein - metabolism / Intellectual disabilities / Language disorders / Male / Medicine and Health Sciences / Membrane Proteins - metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Microcephaly / Microencephaly / Mutation / Neurobiology / Neurons / Neurons - metabolism / Neurosciences / Paralysis / Phagocytosis / Phenotypes / Protein Aggregates - genetics / Protein Aggregation, Pathological - genetics / Protein Aggregation, Pathological - metabolism / Proteins / Receptors, Glutamate - metabolism / Research and Analysis Methods / Seizures / Skin / Spastic paraplegia / Spastic Paraplegia, Hereditary - genetics / Spastic Paraplegia, Hereditary - metabolism / Spastic Paraplegia, Hereditary - pathology / Spasticity / Spinal cord / Spinal Cord - metabolism / Spinal Cord - pathology / trans-Golgi Network - metabolism / Vesicular Transport Proteins - metabolism