Our lab aims to understand the in vivo functions of certain genes identified in neurodegenerative and developmental disorders of the human brain such as schizophrenia, Alzheimer's disease, lissencephaly, autism and mental retardation. We use a variety of molecular and biochemical techniques in conjunction with modeling in rodents and induced pluripotent stem cells (iPSCs) to understand the normal and pathological functions of genes involved in these disorders. By elucidating the normal functions and mechanisms of action of these genes and how mutations cause pathology, we hope to better understand both the fundamental causes of these devastating diseases and the normal development and functioning of the brain.
The development of the mammalian cortex is a complex process that requires the precise coordination of proliferation, cell cycle exit, migration, neurite outgrowth and synaptogenesis. Defects in corticogenesis are thought to underlie aspects of several neuropsychiatric disorders including schizophrenia (SZ). In the past decade, several genes have been identified through both family-based studies as well as through genome-wide analyses that are linked to schizophrenia and related disorders. Perhaps the most widely accepted genetic risk factor in schizophrenia is DISC1 (Disrupted in Schizophrenia-1). A balanced translocation in the DISC1 locus provided the first association of the gene with SZ, and subsequent genetic studies from multiple groups have found additional SZ-related associations within the DISC1 locus. DISC1 is described to have roles in migration, neurite outgrowth, and synapse formation. Our lab is investigating how disruption at the site of the balanced translocation affects DISC1 function in neurodevelopment, and if and how other genes linked to major mental illness intersect with these processes.
Alzheimer's disease (AD) is characterized by the accumulation of extracellular Abeta-containing plaques and intraneuronal hyperphophorylated Tau aggregates. Importantly, distinct brain regions are differentially susceptible to neurodegeneration in AD. Disease progression varies but often begins with gradual loss of episodic declarative memory that correlates with synapse loss and neuritic/neuronal degeneration in the hippocampus and certain regions of the neocortex. Although APP and the enzymes required to cleave APP to generate Abeta are expressed throughout the brain, some regions of the CNS outside of the limbic and cerebral cortices such as cerebellum, thalamus, midbrain and spinal cord are relatively spared by Abeta plaque deposition and synapse loss. Understanding the molecular basis of this selective neuronal vulnerability – one of the key unsolved mysteries of AD - could provide important insights about pathogenic mechanisms and, ultimately, neuroprotective therapies. We are using human iPSCs from control and AD subjects to investigate the mechanism behind the differential vulnerability observed in AD.
Building for Transformative Medicine, Room 100160
60 Fenwood Dr.
Boston, MA 02115