This seminar will begin at 4:00 pm at the Jerome L. Greene Science Center on Columbia University’s Manhattanville campus (L7-119). Light refreshments will be available starting at 3:45 pm.
This month's speakers:
Valeria Gerbino, PhD (Maniatis lab): "TBK1: A Pleiotropic Protein Kinase Impacts Neurodegenerative Disease Progression in an ALS Mouse Model"
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. While the death of motor neurons is an essential feature of the disease, non-cell autonomous mechanisms (deriving mostly from glial cells) contribute to disease progression. We have investigated the effects of ALS associated point mutations in the TBK1 (TANK-Binding Kinase 1) gene by generating knock-in mice bearing missense mutations that cause ALS in humans. While these mutations alone do not lead to an ALS phenotype in the mouse, they profoundly affect the course of neurodegenerative disease progression when crossed into a well-characterized mouse model of ALS. Specifically, we show that TBK1 mutations affect distinct intracellular pathways (autophagy and neuroinflammation) in specific cell types (motor neurons and glia), and at different stages of disease progression.
Enrico Cannavo, PhD (Lomvardas lab): "Dissecting the Molecular Underpinnings of Schizophrenia"
Schizophrenia (SCZ) is a severe neuropsychiatric disorder that affects mental, cognitive and social abilities of ~1% of the human population worldwide. Recent genome-wide association studies in SCZ patients have revealed that SETD1A, a histone methyltransferase, is a key SCZ susceptibility gene. To gain insights into the molecular mechanisms that lead to the onset of SCZ, we studied the effect of Setd1a mutations on the mouse brain. Our results show that the mouse model carrying heterozygous mutations of Setd1a exhibits major morphological and cortical synaptic defects that are accompanied by specific deficits in working memory, thus recapitulating SCZ-related alterations. In particular, Setd1a is recruited to enhancers that specifically regulate the gene expression of pyramidal neurons of the murine prefrontal cortex. The genetic reinstatement of the expression of Setd1a in adult mice partially rescues the behavioral deficits, suggesting that a functional rescue of Setd1a activity represents a feasible therapeutic solution. Since there are no known pharmacological activators for Setd1a lysine methyltransferase activity, we sought to identify pharmacologically tractable lysine de-methylases that antagonize the action of Setd1a. We discovered that LSD1, a lysine demethylase that reverses Setd1a-dependent lysine methylation, has overlapping genomic targets with Setd1a. Strikingly, treatment of primary neurons and Setd1a mutant mice with LSD1 inhibitors rescues morphological and SCZ-related behavioral defects caused by Setd1a mutations.