Leucine-rich repeat and Ig domain-containing protein 1 (LINGO1)

Leucine-rich repeat and Ig domain-containing protein 1 (LINGO1) is a transmembrane protein expressed exclusively in the central nervous system, primarily in neurons and oligodendrocytes (UniProt Q96FE5). Structurally, it contains an extracellular leucine-rich repeat (LRR) domain and an immunoglobulin (Ig) domain, which are essential for its protein-protein interactions within the Nogo-66 receptor 1 (NgR1) signaling complex (Mi et al., 2004, Nature Medicine). LINGO1 serves as a critical negative regulator of axonal regeneration and oligodendrocyte differentiation, activating RhoA to inhibit neurite outgrowth in response to myelin-associated inhibitors (Jepson et al., 2012). In pathological conditions such as multiple sclerosis, LINGO1 is often upregulated, contributing to the failure of remyelination and the progression of permanent neurological disability (Rudick et al., 2008, Lancet Neurology). Therapeutic strategies have focused on using monoclonal antibodies, such as opicinumab (BIIB033), to block LINGO1 activity and promote the repair of myelin sheaths (Cadavid et al., 2017, Lancet Neurology). While preclinical models showed significant promise for neuroprotection and repair, clinical trials in multiple sclerosis have struggled to meet primary efficacy endpoints, highlighting the complexity of remyelination in humans (Mullard, 2016, Nature Reviews Drug Discovery). Beyond demyelinating diseases, LINGO1 is also implicated in the pathogenesis of Parkinson's disease and essential tremor, making it a broad target of interest for neurodegenerative disorders (Inoue et al., 2007, PNAS).

Other names

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1LERN1LRRN6AUNQ201Leucine-rich repeat neuronal protein 1Leucine-rich repeat neuronal protein 6A

Antagonism of LINGO1 to block its inhibitory signaling through the Nogo-66 receptor 1 (NgR1) complex, thereby promoting oligodendrocyte precursor cell differentiation and axonal remyelination.