Description of Research Expertise

While the number of genetic variants associated with developmental brain disorders has exponentially increased, the pathogenic effect for most of them remains unknown, hindering progress in diagnosis and treatment. At Akizu Lab we integrate human genetics with functional studies performed in human pluripotent stem cells (hPSC) and animal models to transform genetic discoveries into novel insights on how genetic variants induce pathology. Our findings enhance the care and management of individuals affected by brain disorders, reveal genetic and epigenetic mechanisms underlaying human brain development and uncover factors that provide selective vulnerability to developing neurons. Our current projects are focused in four lines of research:

1-Uncovering the causes of neurodevelopmental disorders, including autism and intellectual disabilities. Through collaborations with clinical geneticists worldwide, our lab is at the forefront of identifying genetic causes that inform novel diagnoses and treatments for neurodevelopmental disorders (Gracia-Diaz et al., Nat Commun 2023; Li et al., J Clin Invest 2024). Although these disorders are highly heritable, the underlying causes are often complex and include gene and environment interactions that we continuously survey in the lab (Saade et al., Cell Stem Cell 2020).

2-Revealing chromatin-mediated epigenetic mechanisms that lead to neuronal diversity generation in the human brain. Variants in genes encoding chromatin regulators are recurrently associated with neurodevelopmental disorders. Focusing on the Polycomb Repressive Complex 2, a chromatin regulatory complex involved in the epigenetic transmission of cellular identity, our work aims to uncover how diverse chromatin machineries cooperate to determine neuronal subtypes during brain development and how their disruption causes disease (Akizu et al., Development 2010; Akizu et al., Open Biology 2016; Gracia-Diaz et al., Nat Commun 2023).

3-Elucidating mechanisms that confer selective vulnerability to neurodegeneration in developmental brain disorders. The developing human brain is exquisitely sensitive to metabolic dysregulation. Founded on two childhood neurodegenerative disorders of the posterior brain that we genetically defined (Akizu et al., Cell 2013; Akizu et al., Nat Genet 2015), our work aims to unlock how metabolic enzyme polymerization protects neurons from degeneration (Flores et al., BioRxiv 2024) and why the cerebellum is selectively vulnerable to lipid and lysosome homeostatic defects (Zhou and Sanchez et al., JCI Insights 2024).

4-Discovering treatments for neurodevelopmental disorders. Despite evidence demonstrating that neurodevelopmental disorders are treatable, successful treatments are still scarce. Leveraging our mechanistic studies, we aim to develop innovative strategies to treat these disorders. In collaboration with the GoldbergNeurolab at the Children’s Hospital of Philadelphia, we contributed to their efforts in unraveling a targeted therapy that improves seizures and motor behavioral defects in a mouse model of Progressive Myoclonus Epilepsy (Feng et al., Cell Rep Med. 2024). We are also developing novel epigenetic treatments for neurodevelopmental disorders.


CURRENT LAB MEMBERS
Thomas Roule, Ph.D., Postdoctoral Fellow roulet@chop.edu
Vanessa B. Sanchez, Neuroscience graduate group student, vssnchez@pennmedicine.upenn.edu
Lilly Ryll, Neuroscience graduate group student, Lilly.Ryll@Pennmedicine.upenn.edu
Jasmine Akoto, Genetic and Epigenetic graduate group student, Jasmine.Akoto@Pennmedicine.upenn.edu
James Bauer, Neuroscience graduate group student, James.Bauer@Pennmedicine.upenn.edu
Teresa Jimenez, Lab Manager, jimenezsat@chop.edu
Stephanie Gagnon, Stem Cell Technician, gagnons@chop.edu