Abstract Details

Title Adaptor Protein Complex 4 Deficiency: A Paradigm of Complex Hereditary Spastic Paraplegia Associated With Defective Protein Trafficking

Topic Child Neurology and Developmental Neurology

Presentation(s) S19 - Child Neurology: Updates in Autism, Migraine, MS, and Stroke (4:58 PM-5:09 PM)

Poster/Presentation
Number 009

Background Loss of AP-4 leads to prototypical yet poorly understood forms of complex HSP.

Objective Bi-allelic loss-of-function variants in the subunits of the adaptor protein complex 4 (AP-4) lead to hereditary spastic paraplegia (HSP). Aims of this translational study include: 1) to develop a natural history study for AP-4-HSP; 2) to generate AP-4-HSP induced pluripotent stem cells (iPSC); 3) to differentiate these iPSCs into cortical neurons; 4) to characterize neurons with respect to AP-4-related cellular phenotypes.

Design/Methods A combination of clinical characterization and cell biology, biochemistry, pharmacology and high-content imaging to evaluate clinical and cellular characteristics of AP-4-HSP.

Results We report the clinical, molecular and imaging characteristics of 100 individuals with AP-4-HSP. Affected children present with developmental delay/intellectual disability, microcephaly, seizures, progressive spasticity, dystonia and cognitive decline. Key radiographic features include thinning of the corpus callosum and loss of periventricular white matter. We identify several AP-4-related phenotypes in fibroblasts. We find that the autophagy protein ATG9A is a cargo of AP-4 and that AP-4 is required for the intracellular distribution of ATG9A. Loss of AP-4 leads to accumulation of ATG9A in the trans-Golgi-network and depletion from other cellular compartments. Overall ATG9A protein levels are increased. We find that baseline autophagic flux as well as the number and size of autophagosomes are unchanged. Mitochondrial membrane potential and mass remain unchanged. Following the generation of iPSCs from AP-4-HSP patients and controls, we have differentiated excitatory cortical neurons by inducing NGN2 expression. We find that AP-4 related phenotypes are detectable in these neurons, enabling the development of a phenotypic screen for novel therapeutic targets.

Conclusions Through a cross-sectional analysis we have defined the core clinical, molecular and radiographic features of AP-4-HSP. We have also identified several cellular phenotypes of AP-4 deficiency. Use of iPSC-derived cortical neurons from AP-4-HSP patients to support a small-molecule screening may identify targeted therapies.

Authors/Disclosures
Darius Ebrahimi-Fakhari, MD, PhD (Boston Children'S Hospital) PRESENTER	Dr. Ebrahimi-Fakhari has received personal compensation in the range of $0-$499 for serving as a Consultant for Alcimed Inc.. The institution of Dr. Ebrahimi-Fakhari has received research support from CureAP4 Foundation, CureSPG50 Foundation, Spastic Paraplegia Foundation, Manton Center for Orphan Disease Research, BPAN Warriors Foundation, NIH/NINDS. Dr. Ebrahimi-Fakhari has received publishing royalties from a publication relating to health care.
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Mustafa Sahin, MD, PhD (Boston Children'S Hospital)	Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Regenxbio . Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Centene. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for PTEN Research. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Sahin has received research support from NIH. The institution of Dr. Sahin has received research support from Tuberous Sclerosis Alliance. The institution of Dr. Sahin has received research support from Charities Aid Foundation. The institution of Dr. Sahin has received research support from Simons Foundation Autism Research Initiative. The institution of Dr. Sahin has received research support from Aucta Pharmaceuticals . The institution of Dr. Sahin has received research support from Loulou Foundation.

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