Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models.
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.
Inoue
Haruhisa
H
Neuroregeneration Laboratories, Udall Parkinson's Disease Center of Excellence, Harvard Medical School and McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
Lin
Ling
L
Lee
Xinhua
X
Shao
Zhaohui
Z
Mendes
Shannon
S
Snodgrass-Belt
Pamela
P
Sweigard
Harry
H
Engber
Tom
T
Pepinsky
Blake
B
Yang
Lichuan
L
Beal
M Flint
MF
Mi
Sha
S
Isacson
Ole
O
D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
C482293:LINGO1 protein, human; C523678:LINGO1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D004298:Dopamine