The overarching goal of the Fallini Lab is to dissect the molecular and cellular changes that occur in postmitotic neurons during aging and in pathological conditions, such as Amyotrophic Lateral Sclerosis, Frontotemporal Dementia (ALS/FTD) and Alzheimer’s disease.
Our current research is focused on investigating the crosstalk between the actin cytoskeleton, a regulator of cell morphology and structural integrity, and the nuclear pore, the master regulator of protein and RNA shuttling in and out of the nucleus. To investigate these questions, we have established patient-derived induced pluripotent stem cell (iPSC) culture and differentiation into human cortical and motor neurons, an exceptionally valuable and physiologically relevant system to study human disease in a dish. We have several ongoing projects:
The role of the mechanosensitive pathway in the initiation and progression of ALS
Cells are tightly connected to their environment and very sensitive to changes in mechanical strain exerted on the cell from their surroundings. While these mechanisms are known to regulate cell differentiation and survival in dividing cells, little is known about their relevance to neuronal maintenance, particularly during aging.
Analysis of transcriptional and proteomic changes in cortical and motor neurons carrying
The nuclear and cytoplasmic compartments are characterized by wildly different protein composition. The maintenance of this compartmentalization depends on the functional integrity of the nuclear pore, the largest protein assembly in the cell. Disruption of nuclear pores has been recently identified as a key driver of disease in multiple neurodegenerative diseases. Our research aims at defining the downstream consequences of nuclear pore disruption on the nucleocytoplasmic distribution of regulatory proteins and the ability of neurons to modulate their transcriptional response to positive and negative stimulations.
Ischemic stress impacts neuronal survival by altering nuclear pore function
Stroke is an established risk factor for Alzheimer’s disease, but the molecular mechanisms driving this link are unclear. Our research aims at defining the cellular consequences of acute ischemia that can set the stage for chronic neurodegeneration.