Dr Jolly is head of the Neurobiology Research Group and investigates the genetic, molecular, cell and developmental processes which underpin brain development. The overarching goal is to provide patients with neurodevelopmental disorders (NDDs) clear treatment options tailored to underlying genetic mechanisms. The key aspects are therefore to (1) Identify the underlying genetics causes, and (2) Discover tailored therapies. The bridge between these two aspects requires an understanding of how the genes involved in NDDs actually control the development of the brains. The major research areas are to develop technologies to discover causative mutations, apply patient, stem and neuronal cell of brain development to understand gene function, and discover new therapeutics and biomarkers.

Neurodevelopmental Disorders (NDDs) including e.g. intellectual disability, autism spectrum disorder, and movement disorders among others affect ~2% of the world’s population. In developed countries, genetic mutation is the common cause, and cannot always be prevented. With ~1000 genes, and 10,000s of variants implicated in NDDs, understanding each gene/variant function is a major impediment to developing personalised medicines. Our strategy is to target ‘points of convergence’ that exist between NDDs of different genetic origin and study them to identify and develop new therapeutic approaches. We have discovered and studied the involvement of cellular degradation pathways in NDDs which serve as molecular points if convergence. These pathways include both Non-sense Mediated mRNA Decay Pathway (NMD) which regulates mRNA degradation, and protein ubiquitylation which regulates protein degradation. Study and manipulation of these pathways has the potential to inform and influence brain pathologies of NDDs from diverse genetic origins.

Project 1 Nonsense Mediated mRNA Decay: Dr Jolly discovered that mutations in genes encoding the core factors of the Nonsense Mediated mRNA Decay (NMD) factors cause neurodevelopmental disorders. He pioneered how NMD controls stem cell and neuronal cell function. Dr Jolly now leads projects funded by NHMRC Ideas Grant (2021-24) and Sanfilippo Foundation (2021-2022) to investigate and harness the NMD pathway to treat genetic disease caused by nonsense mutations which cause 13% of all genetic diseases.

This research aims to understand the role of NMD during brain development and predict & alleviate outcomes of diseases caused by nonsense mutations. It is underpinned by the development tools to quantify NMD using human biomarkers and engineered biosensors to permit tracking of the NMD pathway in cells and organisms and aid the identification of drugs molecules to modify NMD.

Aim 1. Study the impact of compromised NMD function on brain development.

Aim 2. Use live-cell NMD biosensors to track NMD during development.

Aim 3. Identify NMD biomarkers that predict disease severity and responsiveness to therapies.

Aim 4. Identify FDA approved NMD inhibitory molecules.

Project 2: Protein Degradation: Dr Jolly has been investigating ubiquitin dependent protein degradation by understanding the process of protein de-ubiquitination in the context of brain development. He has >20 years expertise in the field. He has defined clinical syndromes associated with defective de-ubiquitination, developed tools to help diagnose patients,  established a global collaborative network of clinicians and scientists, established a patient support group, and discovered how protein deubiquitination is essential for stem and neuronal cell function. His research is translating this knowledge to overcome a common genetic mechanism known as haploinsufficiency, which relevant to ~3000 genetic diseases, and driven by loss of protein dosage.

This research investigates how loss protein dosage can be controlled ubiquitin dependent degradation during brain development and homeostasis.

Aim 1. Identify brain protein networks whose abundance is controlled by deubiquitinating enzymes.

Aim 2. Identify mechanisms that activate deubiquitinating enzymes

Aim 3. Antagonise the ubiquitin proteasome system to overcome effects of haploinsufficiency.

Project 3: Discovery of disease causing splice altering variants. To date, more than 2000 genes are implicated in Neurodevelopmental Disorders (NDDs). Whilst many different types of variants can cause detriment to NDD gene function, those impacting mRNA splicing and processing are both among the most difficult to identify from DNA sequence alone, and have great potential to be ‘treatable’ through development of new generation antisense oligo therapies among others. Indeed, many NDD patients go undiagnosed as the molecular action of the gene splicing variants cannot be accurately assessed due to the inability to test the variant(s) effect in the context of the living cell of the patient. Close to 500 NDD genes cannot be robustly assayed in patient-derived blood and skin cells because they are simply not expressed. We developed a technology based on modified CRISPR dCas9 gene editing that enables the study of silent genes in patient-derived cells. We will develop and apply this technology to provide new diagnostic avenues including to evaluate the molecular mechanisms of variants that alter mRNA processing and/or degradation of silent NDD genes.

Aim 1: Identify the silent neurodevelopmental disorder genes conducive to dCas9 transactivation.

Aim 2. Identify the silent neurodevelopmental genes expressed in neurons derived by transdifferentiation.

Aim 3. Analyse the pathogenicity of splicing variants in neurodevelopmental disorder patient cell lines.