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Our research is focused upon these fundamental questions:

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, causing progressive loss of motor neurons, weakness, and death within 3-5 years1,2. Over ⅓ of patients with ALS also exhibit behavioral, social, or language abnormalities suggestive of a type of dementia known as frontotemporal dementia (FTD)3,4. Interestingly, approximately 15% of patients with FTD demonstrate a motor neuron disease indistinguishable from ALS, suggesting that ALS and FTD may be fundamentally related to one another5,6. In support of this hypothesis, post-mortem studies demonstrated that the majority of ALS and FTD share a common pathology, marked by the deposition of a protein known as TDP437. Moreover, mutations in several genes cause ALS, FTD, or both, characterized by TDP43-related neurodegeneration. Mutations in the gene encoding TDP43 (TARDBP) also result in ALS and less often FTD8, consistent with the central role of TDP43 in disease pathogenesis.

TDP43 is an essential nuclear protein that functions in RNA transcription, translation, transport and degradation9 . In preliminary studies, we established a faithful neuronal model of ALS and FTD, and verified that this system recapitulates essential features of disease in vitro10. 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. An identical cytoplasmic redistribution of TDP43 is characteristic of degenerating neurons from patients with ALS and FTD7, confirming the significance of the phenomenon and directly implicating it in the pathogenesis of disease. 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.

Both ALS and FTD are progressive neurodegenerative diseases. However, we know little about how disease spreads from the initial site of onset to other cells or regions of the central nervous system (CNS). A thorough understanding of how pathologic processes propagate within the CNS is critical if we are to prevent or stop neuronal loss once it has begun. Therefore, 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 previous 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 (Barmada et al., submitted). We are also exploring strategies that modulate RNA processing as potential therapies in these conditions11, since dysregulated RNA processing is a final common mediator of neuronal toxicity in ALS and FTD12.

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 humans13,14. The efficacy of experimental therapies for ALS or FTD in human clinical trials has been disappointing; inadequate pre-clinical testing, imprecise model systems, or both have contributed to high rates of failure. Human stem cell-derived neurons are the most genetically precise disease models available15, 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 neurons16 and astrocytes17 derived from human induced pluripotent stem cells and primary cultures. Many of our experiments involve automated fluorescence microscopy, a powerful technology initially introduced by Dr. Steve Finkbeiner of the Gladstone Institutes and UCSF18,19, capable of simultaneously imaging thousands of neurons or glia and prospectively following these cells over extended periods of time. The ability to longitudinally assay cell fate under precisely controlled conditions permits us to make conclusions regarding cause and effect relationships that are otherwise impossible to approach using conventional microscopy or biochemical techniques. 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.

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  2. Bedlack, R. S. Amyotrophic lateral sclerosis: current practice and future treatments. Curr Opin Neurol 23, 524-529 (2010).
  3. Lomen-Hoerth, C. et al. Are amyotrophic lateral sclerosis patients cognitively normal? Neurology 60, 1094-1097 (2003).
  4. Murphy, J. M. et al. Continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Arch Neurol 64, 530-534 (2007).
  5. Rabinovici, G. D. & Miller, B. L. Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs 24, 375-398 (2010).
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  9. Buratti, E. & Baralle, F. E. Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 13, 867-878 (2008).
  10. Barmada, S. J. et al. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J Neurosci 30, 639-649 (2010).
  11. Armakola, M. et al. Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nature Genetics 1–10 (2012). doi:10.1038/ng.2434
  12. Ugras, S. E. & Shorter, J. RNA-Binding Proteins in Amyotrophic Lateral Sclerosis and Neurodegeneration. Neurology Research International 2012, 1-5 (2012).
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  14. Turner, B. J. & Talbot, K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol 85, 94-134 (2008).
  15. Dolmetsch, R. & Geschwind, D. H. The Human Brain in a Dish: The Promise of iPSC-Derived Neurons. Cell 145, 831-834 (2011).
  16. Bilican, B. et al. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci USA 109, 5803–5808 (2012).
  17. Serio, A. et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc Natl Acad Sci USA (2013). doi:10.1073/pnas.1300398110
  18. Arrasate, M. & Finkbeiner, S. Automated microscope system for determining factors that predict neuronal fate. Proc Natl Acad Sci USA 102, 3840-3845 (2005).
  19. Arrasate, M. et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805-810 (2004).