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Published online on August 28, 2007, 10.1073/pnas.0700901104 OPEN ACCESS ARTICLE


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Medical Sciences
Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models

( dopamine neuron | substantia nigra | degeneration | neuroprotection | axon )

Haruhisa Inoue *, Ling Lin *, Xinhua Lee {dagger}, Zhaohui Shao {dagger}, Shannon Mendes *, Pamela Snodgrass-Belt {dagger}, Harry Sweigard {dagger}, Tom Engber {dagger}, Blake Pepinsky {dagger}, Lichuan Yang {ddagger}, M. Flint Beal {ddagger}, Sha Mi {dagger}{sect}, and Ole Isacson *{sect}

*Neuroregeneration Laboratories, Udall Parkinson's Disease Center of Excellence, Harvard Medical School and McLean Hospital, 115 Mill Street, Belmont, MA 02478; {dagger}Department of Discovery Biology, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142; and {ddagger}Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East Sixty-Eighth Street, New York, NY 10021

Edited by Tomas Hökfelt, Karolinska Institutet, Stockholm, Sweden, and approved July 22, 2007 (received for review February 1, 2007)

The nervous system-specific leucine-rich repeat Ig-containing protein LINGO-1 is associated with the Nogo-66 receptor complex and is endowed with a canonical EGF receptor (EGFR)-like tyrosine phosphorylation site. Our studies indicate that LINGO-1 expression is elevated in the substantia nigra of Parkinson's disease (PD) patients compared with age-matched controls and in animal models of PD after neurotoxic lesions. LINGO-1 expression is present in midbrain dopaminergic (DA) neurons in the human and rodent brain. Therefore, the role of LINGO-1 in cell damage responses of DA neurons was examined in vitro and in experimental models of PD induced by either oxidative (6-hydroxydopamine) or mitochondrial (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity. In LINGO-1 knockout mice, DA neuron survival was increased and behavioral abnormalities were reduced compared with WT. This neuroprotection was accompanied by increased Akt phosphorylation (p-Akt). Similar neuroprotective in vivo effects on midbrain DA neurons were obtained in WT mice by blocking LINGO-1 activity using LINGO-1-Fc protein. Neuroprotection and enhanced neurite growth were also demonstrated for midbrain DA neurons in vitro. LINGO-1 antagonists (LINGO-1-Fc, dominant negative LINGO-1, and anti-LINGO-1 antibody) improved DA neuron survival in response to MPP+ in part by mechanisms that involve activation of the EGFR/Akt signaling pathway through a direct inhibition of LINGO-1's binding to EGFR. These results show that inhibitory agents of LINGO-1 activity can protect DA neurons against degeneration and indicate a role for the leucine-rich repeat protein LINGO-1 and related classes of proteins in the pathophysiological responses of midbrain DA neurons in PD.

Author contributions: H.I. and L.L. contributed equally to this work; H.I., L.L., S.M., and O.I. designed research; H.I., L.L., X.L., Z.S., S.M., P.S.-B., H.S., T.E., B.P., and L.Y. performed research; X.L., Z.S., M.F.B., and S.M. contributed new reagents/analytic tools; H.I., L.L., Z.S., P.S.-B., S.M., and O.I. analyzed data; and H.I., L.L., S.M., and O.I. wrote the paper.

The authors declare no conflict of interest.

Freely available online through the PNAS open access option.

{sect}To whom correspondence may be addressed.

Sha Mi, E-mail: sha.mi{at}biogenidec.com
Ole Isacson, E-mail: isacson{at}hms.harvard.edu

www.pnas.org/cgi/doi/10.1073/pnas.0700901104
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