LRP4 x AGRN

Last update 08 May 2025

Basic Info

Related Targets

LRP4AGRN

Drugs associated with LRP4 x AGRN

NT-1640

Target

AGRN x LRP4

Mechanism

AGRN stimulators [+1]

Active Org.

Neurotune AG

Originator Org.

Neurotune AG

Active Indication

Sarcopenia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with LRP4 x AGRN

100 Translational Medicine associated with LRP4 x AGRN

0 Patents (Medical) associated with LRP4 x AGRN

166

Literatures (Medical) associated with LRP4 x AGRN

01 May 2025·International Journal of Biological Macromolecules

Agrin-deficient osteocytes disrupt bone tissue homeostasis in male mice

Article

Author: Baron, Roland ; Ramos, Ana Paula ; Rosa, Adalberto Luiz ; Calixto, Robson Diego ; Beloti, Marcio Mateus ; Adolpho, Leticia Faustino ; Souza, Alann Thaffarell Portilho ; Almeida, Adriana Luisa Gonçalves ; Oliveira, Fabiola Singaretti ; Gomes, Maria Paula Oliveira ; Gori, Francesca ; Bighetti-Trevisan, Rayana Longo

Osteocytes are terminally differentiated osteoblasts that secrete molecules that regulate bone-tissue homeostasis. Considering that the extracellular matrix protein agrin (AGRN) is secreted by osteoblasts and modulates their differentiation, we hypothesized that AGRN is also expressed by osteocytes and plays a role in their function and therefore in bone remodeling. To test this hypothesis, we deleted agrin specifically in osteocytes using dentin matrix acidic phosphoprotein 1 (DMP1)-Cre mice (C57/BL6 background) and silenced agrin in vitro using clustered regularly interspaced short palindromic repeats/associated nuclease Cas-9 in the Ocy454 osteocyte cell line. We found that osteocytes express agrin and its receptors, low-density lipoprotein receptor-related protein 4, and α-dystroglycan, and that mice with agrin-deficient osteocytes exhibited lower bone mass and impaired mechanical and chemical properties of bone tissue. Agrin knockdown in Ocy454 cells disrupted osteocyte differentiation and function, which reduced osteoblast and increased osteoclast differentiation in a cell co-culture model. Our results showed that agrin is expressed by osteocytes, which are key regulators of bone mass and its mechanical and chemical properties. These findings indicate that agrin may be a therapeutic target because it is important to maintain the balance of the osteocyte-osteoblast-osteoclast circuit, and consequently, bone tissue homeostasis.

09 Apr 2025·The Journal of Neuroscience

MuSK Regulates Neuromuscular Junction Nav1.4 Localization and Excitability

Article

Author: Christian, Jan L ; Xi, Chengjie ; Arnold, William D ; Wang, Xueyong ; Wharton, Kristi A ; Jaime, Diego ; Fallon, Justin R ; Shahtout, Justin L ; Madigan, Laura A ; Rich, Mark M ; Ewing, Madison D ; Feder, Rita E ; Fish, Lauren A ; Funai, Katsuhiko ; Rich, Kelly A ; Chen, Isabella

The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly, the NMJ transduces nerve action potentials into muscle fiber action potentials (MFAPs). Efficient neuromuscular transmission requires cholinergic signaling, which generates endplate potentials (EPPs), and excitation, the amplification of an EPP by postsynaptic voltage-gated sodium channels (Nav1.4) to generate the MFAP. Compared to the cholinergic component, the signaling pathways that organize Nav1.4 are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as the main organizer of acetylcholine receptors (AChRs), also binds BMPs via its Ig3 domain and shapes BMP-induced signaling. Using mice lacking the MuSK Ig3 domain (“ΔIg3-MuSK”), we probed the role of this domain at the NMJ. NMJs formed in ΔIg3-MuSK animals with pre- and postsynaptic specializations aligned at all ages examined. However, the ΔIg3-MuSK postsynaptic apparatus was fragmented from an early age. Synaptic electrophysiology showed that spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable at WT and ΔIg3-MuSK NMJs. However, single fiber electromyography revealed that nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal, exhibiting jitter and blocking. Nerve-evoked compound muscle action potentials and muscle force were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK NMJs, but not extrasynaptically, indicating that the observed excitability defects result from impaired synaptic localization of this ion channel. We propose distinct, domain-specific roles for MuSK at the NMJ: the Ig1 domain mediates agrin-LRP4-mediated AChR localization, while the Ig3 domain maintains postsynaptic Nav1.4 density, conferring the muscle excitability required to amplify cholinergic signals and trigger action potentials.

06 Feb 2025·Cureus

A Case of Myasthenia Gravis: A Paraneoplastic Syndrome or an Immune-Related Disorder?

Article

Author: Thatikonda, Nithisha ; Fang, Xiang ; Patel, Chilvana ; Thyagarajan, Jaya S ; Almomani, Mohammad H

Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by fatigable muscle weakness. While commonly linked to acetylcholine receptor (AChR) antibodies, other reported antibodies include muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), agrin, striated muscle, myosin, ryanodine receptor, and titin. Notably, titin antibodies are being highlighted for their role in MG pathogenesis, as they have been associated with increased disease severity. Immune checkpoint inhibitors (ICIs), while highly effective for solid tumors, can rarely induce immune-related myasthenia gravis (irMG), a neurological adverse effect with higher mortality than classic MG. We present a case of MG with atypical serology, highlighting the challenges of classifying and treating classic MG, paraneoplastic syndromes, and irMG. A 68-year-old man with a history of stage IV left renal cell carcinoma (RCC) with lung metastases after undergoing left nephrectomy and right segmental lung lobectomy presented with one month of palpebral ptosis, shortness of breath, dysphagia, and generalized muscle weakness. He had recently received two doses of 200 mg pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor. Physical examination revealed bilateral palpebral ptosis, symmetric, primarily proximal weakness, including bulbar and facial muscles with fatigability, and normal reflexes. Serum studies were positive for anti-striated muscle (>1:2560) and anti-titin (>2.71) antibodies, suggesting irMG or a paraneoplastic syndrome, with negative anti-AChR and anti-MuSK antibodies. Computed tomography (CT) of the chest showed no thymic disease. The patient improved with high-dose steroids followed by plasma exchange and intravenous immunoglobulin (IVIG). Repeated striated muscle antibodies were decreased, but anti-titin antibodies were persistently elevated. He is neurologically stable on pyridostigmine 60 mg, 3 liters of nasal cannula oxygen, and nighttime bilevel positive airway pressure (BiPAP) but experiences residual muscle weakness that requires wheelchair use. In summary, we present a case of MG with the presence of titin and striated muscle antibodies in a patient with metastatic RCC undergoing checkpoint immunomodulating therapy. Management remains challenging in patients with underlying malignancy treated with ICIs.

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