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Sami Barmada

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Primary Appointment: Neurology Department
Other PIBS Depts.: Neuroscience
PubMed Name: Barmada S or Barmada SJ
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 DESCRIPTION OF RESEARCH
  We are focused on the pathologic overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and how we can take advantage of the convergence to identify new and effective therapies. To do so, we investigate mechanisms of disease on the level of single cells using fully-automated longitudinal microscopy in mature neurons and astrocytes, derived from primary rodent cultures or human stem cells.

ALS is the most common motor neuron disease, causing progressive loss of motor neurons, weakness, and death within 3-5 years. Over 1/3 of patients with ALS also exhibit behavioral, social, or language abnormalities identical to those found in patients with FTD. At the microscopic level, ALS and FTD share a common pathology, marked by the deposition of a protein known as TDP43. Moreover, mutations in several genes cause ALS, FTD, or both, characterized by the accumulation of TDP43. Mutations in the gene encoding TDP43 (TARDBP) also result in ALS and less often FTD, consistent with the central role of TDP43 in disease pathogenesis.

In preliminary studies, we established a faithful neuronal model of ALS and FTD, and verified that this system recapitulates essential features of disease in vitro. Furthermore, we demonstrated that a mutation in TARDBP associated with familial ALS causes neuronal toxicity through the mislocalization of TDP43 from the nucleus, where it is normally concentrated, to the cytoplasm. One aspect of our current research centers on how disease-related mutations in TDP43 cause cytoplasmic mislocalization, and on the downstream effects of cytoplasmic TDP43 leading to neuronal toxicity.

We are also interested in how and why disease begins– what are the inciting events that trigger the degeneration of neurons in ALS and FTD? Why does ALS affect motor neurons, and FTD target layer V cortical neurons? A part of the laboratory is dedicated to investigating the intrinsic (cell-autonomous) and extrinsic (non cell-autonomous) contributions to neuronal survival in ALS and FTD, and the selective vulnerability of neuronal subtypes to disease-related stimuli. Our laboratory is also devoted to determining how the pathologic process in ALS and FTD spreads among susceptible neurons.

Patients with ALS and FTD, their families, and their physicians all agree that there is a crucial need for new and effective treatments. To this end, we are investigating therapeutic strategies capable of improving neuronal survival. In ongoing studies, we have shown that stimulation of autophagy, an endogenous pathway capable of degrading long-lived proteins and organelles, enhances the metabolism of TDP43 and improves neuronal survival in models of ALS and FTD. We are also exploring strategies that modulate RNA processing as potential therapies in these conditions, since dysregulated RNA processing is a final common mediator of neuronal toxicity in ALS and FTD.

Today, one of the biggest obstacles to the development of novel therapies is the lack of faithful translation from preclinical models of neurodegenerative diseases to humans. Human stem cell-derived neurons are the most genetically precise disease models available, and therefore have the potential to transform the current state of therapeutics development for both ALS and FTD. We model and investigate mechanisms of disease using neurons and astrocytes derived from human induced pluripotent stem cells and primary cultures. To do so, we take advantage of fully automated longitudinal fluorescence microscopy, a platform that allows for high-throughput and high-content prospective analyses of cell fate. The system is inherently flexible and easily adaptable to an impressive array of investigations, and the range of applications continues to expand as the repertoire of physiologic reporters grows and the imaging technology evolves.