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

Inoue, Haruhisa, Lin, Ling, Lee, Xinhua, Shao, Zhaohui, Mendes, Shannon, Snodgrass-Belt, Pamela, Sweigard, Harry, Engber, Tom, Pepinsky, Blake, Yang, Lichuan, Beal, M. Flint, Mi, Sha, Isacson, Ole
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.36 pp. 14430-14435
Parkinson disease, animal models, antagonists, antibodies, brain, disease models, epidermal growth factor receptors, humans, knockout mutants, mice, neurites, neuroprotective effect, neurotoxicity, patients, phosphorylation, signal transduction, tyrosine
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.