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

Abstract

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. dopamine neuron ͉ substantia nigra ͉ degeneration ͉ neuroprotection ͉ axon N ew therapeutics are required that simultaneously preserve dopamine (DA) neurons and their functional connections to limit or eliminate the progression of the movement disorder of Parkinson's disease (PD) (1, 2). Several growth factors normally active in cell growth and survival during brain development have been shown to provide protection against cell death in animal models of PD (1-5). The phosphoinositide 3-kinases (PI3-Ks) and Akt (protein kinase B) signaling pathways have been shown to participate in such growth factor actions (1, 2, 5, 6). Recent studies also suggest that some leucine-rich repeat (LRR) Ig-containing proteins can influence growth factors by modulating EGF receptor (EGFR) signaling-related pathways (7,8). LINGO-1 is a LRR-Ig protein first identified as a critical component of the NogoR1-p75NTR complex in RhoA activation, and it is responsible for some inhibition of axonal regeneration by myelin-associated factors (9, 10). Unlike NogoR1, LINGO-1 gene expression is increased when adult nerve cells are exposed to traumatic injuries (9), indicating that LINGO-1 may be involved in cell injury responses. LRRK2, another LRR protein, was recently genetically linked to PD and Lewy body disease (11, 12). As we describe here, LINGO-1 appears to regulate neurite growth and the structural integrity of neurons, in analogy with LRRK2 (9, 13).In this study, elevated LINGO-1 levels were found after selective experimental damage to DA nerve terminals in the striatum of mice, and increased expressed levels of LINGO-1 were found in the substantia nigra (SN) of some PD patients. Using methods that reduced or eliminated the negative actions of LINGO-1, we demonstrate that midbrain DA neuron survival, growth, and function improve in primary in vitro cultures and in vivo experimental models of parkinsonism in mice. We also show that LINGO-1 normally binds to EGFR and negatively regulates the EGFR/Akt signaling pathway in cells and tissues relevant to these studies. Fig. 4 B and C). LINGO-1 is expressed in remaining DA neurons in the SN of PD patients (SI Fig. 4 A and B)....

Amino-Nogo-A antagonizes reactive oxygen species generation and protects immature primary cortical neurons from oxidative toxicity

“…Previous studies have revealed that many known regulatory roles of Nogo-A rely on Nogo-66-NgR/p75/ LINGO-1-RhoA-ROCK pathway, 2 which are reported to play important roles in several neuronal death models. [17][18][19][20] We then assessed whether these components participated in the neuroprotection. Cell death assay showed no significant difference from that of control with several different signaling blockers, such as 1E8 and 2B3 mAb against Nogo-A, 15 TAT-NEP1-40 (Nogo extracellular peptide, residues 1-40), 20 soluble LINGO-1-Fc 18 and TAT-C3 protein (Figures 4a-d).…”

Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

“…35 Overexpression of LINGO1 is also observed in several neuronal disorders including multiple sclerosis, Parkinson disease, and essential tremor. 36 Various association studies have also shown the role of LINGO1 variants with essential tremor and Parkinson's disease. 37 Moreover, inhibitory anti-LINGO1 antibodies promoted illegitimate oligodendrocyte differentiation and myelination of neurons by inhibiting the function of LINGO1.…”

LINGO-1 Receptor Promotes Neuronal Apoptosis by Inhibiting WNK3 Kinase Activity

“…For example, the binding of LINGO-1 to the EGFR has been shown to directly inhibit EGFR expression. This results in a dampening of PI3K/Akt signaling, which has been shown to protect dopaminergic neurons from apoptosis (12). LINGO-1 has also been shown to associate with TrkB in the regulation of RGC survival (30).…”

“…For example, blocking LINGO-1 function improves midbrain dopaminergic neuron survival in an animal model of Parkinson disease (12), increases RGC survival in a rat model of chronic glaucoma (11), and protects cerebellar granule neurons from low potassiuminduced apoptosis (13). Moreover, genetic analysis suggests that the LINGO1 gene may be an attractive target when developing therapies for the treatment of neurodegenerative diseases that are thought to be characterized by neuronal apoptosis (28,29).…”

“…LINGO-1 antagonists were shown to provide similar neuroprotective effects to midbrain dopaminergic neurons both in vitro and in vivo. These neuroprotective effects were shown to result from activation of the EGFR/Akt signaling pathway through direct inhibition of LINGO-1 binding to the EGFR (12). In a model of * This work was supported by National Key Basic Research Program Grant retinal ganglion cell (RGC) injury, exogenously added soluble LINGO-1-Fc and anti-LINGO-1 antibody 1A7 significantly reduced RGC loss after ocular hypertension and also promoted RGC survival after optic nerve transection (11).…”