Ole Isacson, M.D. (Dr.Med.Sci.)

McLean Hospital
MRC 130, Center for Neuroregeneration Research
115 Mill St
Belmont, MA 02478
Telephone: 617-855-3283
Email: isacson@hms.harvard.edu
Predocs: 1 Postdocs: 12 Completed PhD's: 3

This program focuses on the mechanisms and dynamics of neuronal regeneration (1,3,5), degeneration and protection (2,3) with particular emphasis on the neurodegenerative disorders like Parkinson's, Huntington's, Alzheimer's and ALS. Our understanding of regeneration and plasticity of the mammalian nervous system has developed greatly over the last decade, due to basic research in rats following implantation of fetal, cultured or genetically engineered cells into the adult brain . While the adult brain previously was thought of as a non-regenerative system for pathway formation, recent studies show how dissociated primordial neurons implanted or induced in the adult central nervous system can grow to reconnect neuronal pathways and integrate in a molecular and physiological fashion. Thus, anatomical, neurochemical, molecular and behavioral parameters indicate that reconstructive events can take place also in the degenerated adult brain (1-4).

The cellular, physiological and molecular events associated with progressive neuronal death and degeneration in the neurodegenerative diseases are still unknown. We search for causal events involved in maintaining neuronal plasticity and health on a cellular level, by (a); constructing model systems that as closely as possible simulate the regional and cellular degeneration seen in brains with neurodegenerative disease, and (b); testing various factors and conditions that may prevent or reverse degeneration in such models (5-6). These studies combined are likely to yield to a better understanding of regeneration, development and plasticity of the brain both at a cellular and system integration level. In addition, our research may lead to future therapies for neurodegenerative disease.

References:

• Mendez I, Sanchez-Pernaute R, Cooper O, Vinuela A, Ferrari D, Bjorklund L, Dagher A, Isacson O. (2005) Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease. Brain. 128, 1498-1510.
• Bjorklund, L., Pernaute, R.S., Chung, S., Andersson, T., Chen, I.Y.C., McNaught, K.S.P., Brownell, A.-L., Jenkins, B.G., Wahlestedt, C., Kim, K.-S., Isacson, O. (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc. Natl. Acad. Sci. 99, 2344-2349.
• Cooper O. and Isacson O. (2004) Intrastriatal transforming growth factor alpha delivery to a model of Parkinson's disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons. J Neurosci. 24, 8924-31.
• Isacson, O., Seo, H., Lin, L., Albeck, D., Granholm, A.-C. (2002) Alzheimer’s disease and Down’s syndrome: roles of APP, trophic factors and ACh. Trends Neurosci. 25, 79-84.
  Chung, C.Y., Seo, H., Sonntag, K-C. Brooks, A., Lin, L. and Isacson, O. (2005) Cell type specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Hum Mol Genet. 14, 1709-25.
• Inoue H, Lin L, Lee X, Shao Z, Mendes S, Snodgrass-Belt P, Sweigard H, Engber T, Pepinsky B, Yang L, Beal MF, Mi S, Isacson O. (2007) Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson’s disease models. Proc Natl Acad Sci USA 104, 14430-35.