Inhibition of the Leucine-Rich Repeat Protein LINGO-1 Enhances Survival, Structure, and Function of Dopaminergic Neurons in Parkinson's Disease Models

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 36; pp. 14430 - 14435
• Main Authors: Inoue, Haruhisa, Lin, Ling, Lee, Xinhua, Saho, Zhaohui, Mendes, Shannon, Snodgrass-Belt, Pamela, Sweigard, Harry, Engber, Tom, Pepinsky, Blake, Yang, Lichuan, Beal, M. Flint, Mi, Sha, Isacson, Ole
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04.09.2007; National Acad Sciences
• Subjects: Animal models; Animals; Antibodies; Biological Sciences; Brain; Cell death; Cell Line; Cell Survival; Cultured cells; Disease Models, Animal; Dopamine - biosynthesis; Gene Expression Regulation; Humans; Lesions; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Midbrain; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurites; Neurites - metabolism; Neurons; Neurons - cytology; Neurons - metabolism; Parkinson disease; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0700901104

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.