Details

Start of the project: 01.08.2019

Finishing date: 17.05.2023

Title of the project: The role of Slc7a5 in neurodevelopment and neuronal survival

Research topic of the student:  Autism spectrum disorders (ASD) represent a heterogeneous group of genetic disorders often overlapping with other neurological conditions such intellectual disability, ADHD or microcephaly. Previously, we described that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter, has a crucial role in maintaining branched chain amino acid (BCAA) levels in the brain [1]. We identified several patients harboring a homozygous missense mutation in the SLC7A5 gene, who are on the autism spectrum (ASD) and are presented with motor deficits and microcephaly. In Mice, deletion of Slc7a5 from the blood brain barrier endothelial cells leads to decreased levels of BCAAs in the brain, altered cap-dependent translation and severe neurological abnormalities on an electrophysiological and behavioral level. Intracerebroventricular administration of BCAAs partially ameliorated the neurological impairments in adult mutant mice. Now, aiming to dissect the molecular mechanisms underlying the microcephalic phenotype of the patients, we generated conditional knock-out mouse lines (cKO) of Slc7a5 specifically targeting neuroprogenitor cells of the developing brain. These cKO mice are presented with a microcephalic brain, thereby recapitulating the patient’s phenotype. Our recent findings imply that the significant reduction of cortical thickness is caused by an induction of apoptosis within the postnatal cortex affecting mainly upper layer neurons. This indicates a crucial role of Slc7a5 not only in regulating branched chain amino acid levels in the brain, but also for neuronal survival. Thereby, introducing Slc7a5 as a potential drug target for modulating neuronal survival within a pathophysiological context.

[1] Tarlungeanu, D.C., Deliu, E., Dotter, C.P., et al. 2016. Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder. Cell 167(6), 1481-1494.

Lab Rotation project: 15.12.2019-15.02.2020 (8-9 weeks) 

Project titles: Project I: Imaging newly synthesized proteins

Project II: Imaging ribosomal RNA

Lab Host: Johann DANZL, IST

Position after PhD: Regulatory Affairs Manager, W&G group

Lisa Knaus published a first-author paper in Cell:

Knaus LS, Basilico B, Malzl D, Gerykova Bujalkova M, Smogavec M, Schwarz LA, Gorkiewicz S, Amberg N, Pauler FM, Knittl-Frank C, Tassinari M, Maulide N, Rülicke T, Menche J, Hippenmeyer S, Novarino G. Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell. 2023 Mar 24:S0092-8674(23)00215-5. doi: 10.1016/j.cell.2023.02.037.

Link to Publications by Lisa Knaus

Link to video-talk by Lisa Knaus Title: Studying the role of the large neutral-amino acid transporter Slc7a5 in autism spectrum disorder and microcephaly; 24.01.2021