Understanding cellular mechanisms underlying autism and ADHD-linked Neurofibromatosis type 1

About the Project

Lead supervisor:Dr Ines Hahn

Co-supervisors:Prof Will Brackenbury and Dr G Evans

The student will be registered with the Department of Biology

Background: Neurofibromatosis type 1 (NF1) is the most common monogenetic disorder which affect 1/5000 and shows a high prevalence for Autism and ADHD and is caused by loss of neurofibromin, a highly conserved multidomain protein. Loss of neurofibromin (Nf1) additionally leads to cognitive and behavioural deficits as well as electrophysiological abnormalities in patients and animal models. How the functional loss of Nf1 links to molecular mechanisms driving the disorder remains, however, largely unknown. To tackle this, this studentship will elucidate how Nf1 controls neuronal development and maintenance and how loss of Nf1 leads to those functional deficits in neurons. We recently have created Nf1 models using CRISPR/Cas9 that lack functional domains of Nf1. Objectives: The student will a) determine molecular mechnisms how Nf1 controls neurite outgrowth and synapse formation; b) test genetic and chemical interventions to improve neuronal morphology and cell biology.

Novelty and timeliness: As an interdisciplinary supervisory team consisting of a cell biologist, electrophysiologist, stem cell biologists and clinician, we are uniquely placed to drive key findings towards therapeutic approaches. We have recently i) established Drosophila primary neurons as a novel model of Nf1 loss, ii) generated the first Nf1 CRISPR/Cas9 fly lines abolishing functional Nf1 domains that will allow us to explore mechanisms underlying NF1, and iii) patient-derived iPSC cortical neurons which enable us to test interventions identified in flies.

Experimental Approach: Using combinatorial genetics in primary fly neurons, fluorescence microscopy, live-imaging and patch-clamp electrophysiology, the student will: (1) Conduct a structure function analysis to understand how Nf1 controls axonal initiation branching, outgrowth and synapse formation. (2) Determine blocking which downstream pathways is neuroprotective in Nf1-/- fly neurons and patient-derived iPSC neurons. (3) Characterise electrophysiological defects of Nf1 mutants and test if neuroprotective interventions identified in (2) can improve neuronal function and therefore represent a therapeutic strategy for NF1.

The University of York is committed to recruiting future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and we have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.

The Department of Biology holds an Athena SWAN Gold Award. We are committed to supporting equality and diversity and strive to provide a positive working environment for all staff and students.

Entry Requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with any biological, chemical, and/or physical science backgrounds, or students with mathematical background who are interested in using their skills in addressing biological questions.

Programme: PhD in Biomedical Science (3 year)

Start Date: 21 September 2026