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

• DOI: 10.1073/pnas.0700901104
• Publication Date: 2007-08-29T02:44:04Z
• Authors: Haruhisa Inoue; Ling Lin; Xinhua Lee; Zhaohui Shao; Shannon Mendes; Pamela Snodgrass-...; Harry Sweigard; Tom Engber; Blake Pepinsky; Lichuan Yang; M. Flint Beal; Sha Mi; Ole Isacson
• Keywords: Neurite; Oxidopamine

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