Signalling mechanisms in neurodevelopmental disorders

Individuals in the spectrum [referred to as autism spectrum disorder (ASD)] are often affected by behavioural conditions like impairments in social interactions and communication or reveal repetitive and restricted interests. Furthermore, hyper- or hyposensitivity to external stimuli combined with anxiety, altered motor skills, epilepsy or macro-/microcephaly may occur and vary between individuals.

Whilst most cases are idiopathic, several genes with a high prevalence for ASD have been described. Our lab specifically focuses on phosphatase and tensin homologue (PTEN), of which mutations were identified in autistic children with macrocephaly. In its canonical function, PTEN antagonises phosphatidylinositol-3-phosphate kinase (PI3K) signalling, but also acts as a protein phosphatase in the cytosol and nucleus, e.g. regulating cytoskeletal rearrangement, DNA repair or gene expression. Though the connection between PTEN mutations and ASD was shown in the early 2000’s, little is known about the spatiotemporal molecular mechanisms underlying PTEN dysfunction during neurodevelopment.

By employing a large spectrum of methods (e.g., laser microscopy, cell sorting, biochemical techniques, mass spectrometry, RNA-sequencing, electrophysiological recordings and behavioural assays) to cell lines, primary neurons and mouse models, we aim at characterising altered intrinsic and extrinsic signalling mechanisms between neurotypical and PTEN-ASD conditions.

Key Publications

Ledderose JMT, Benitez JA, Roberts AJ, Reed R, Bintig W, Larkum ME, Sachdev RNS, Furnari F, Eickholt BJ. The impact of phosphorylated PTEN at threonine 366 on cortical connectivity and behaviour. Brain 2022;145(10):3608-3621. DOI:10.1093/brain/awac188

Rademacher S, Eickholt BJ. PTEN in Autism and Neurodevelopmental Disorders. Cold Spring Harb Perspect Med 2019;9(11). DOI:10.1101/cshperspect.a036780

Sebastian Rademacher
Marie Chiara Rehm
Aasha Meenakshisundaram
Timothy A. Zolnik
Zoltan Molnar (Oxford, UK)
Matthew Larkum (Berlin, Germany)
Christian Rosenmund (Berlin, Germany)
Angela Kaindl (Berlin, Germany)