SORL1

What is SORL1 protein?

SORL1 (sortilin related receptor 1) gene is a protein coding gene which situated on the long arm of chromosome 11 at locus 11q24. It is a large, multi-domain containing, membrane-bound receptor that plays a significant role in endosomal sorting of proteins between the trans-Golgi network, endosomes, and the plasma membrane. SORL1 is composed of several distinct domains and belongs to both the low-density lipoprotein receptor (LDLR) family and the vacuolar protein sorting 10 (VPS10) domain receptor family. The level of SORL1 was found to be decreased in the AD brain, which positively correlated with β-amyloid (Aβ) accumulation. SORL1 protein is consisted of 2214 amino acids and its molecular mass is approximately 248.4 kDa.

What is the function of SORL1 protein?

SORL1 is involved in the sorting of proteins within the endosomal system, helping to direct proteins to either the lysosomal degradation pathway or back to the cell surface. SORL1 plays a crucial role in the trafficking and processing of APP. It helps to regulate the transport of APP away from the endosome, thereby influencing the production of amyloid-beta (Aβ) peptides, which are implicated in Alzheimer's disease. SORL1 works together with the retromer trafficking complex to regulate the recycling of APP out of the endosome, contributing to endosomal swelling and APP misprocessing when SORL1 function is compromised. SORL1's expression can significantly impact the neuronal recycling pathway, with loss of SORL1 causing endosomal traffic jams and enlargement of early and recycling endosomes.

Fig1. Intracellular trafficking path for SORLA. (Vanessa Schmidt, 2017)

SORL1 Related Signaling Pathway

SORL1 is involved in the occurrence and development of late-onset Alzheimer's disease by interacting with different cytoplasmic adapters to affect the transport and metabolism of β-amyloid precursor proteins in cells. The interaction between SORL1 and brain-derived neurotrophic factor may affect the survival and function of neurons, and thus the progression of AD. SORL1 may be involved in regulating the expression and function of receptors on the cell surface, affecting the signaling of neurotransmitters. SORL1 may affect APP processing and Aβ production through Rho kinase signaling pathway. SORL1's interaction with GGA protein may affect its transport and recycling in the cellular endosome.

SORL1 Related Diseases

SORL1 gene is closely related to the pathogenesis of late-onset Alzheimer's disease (AD) and is a high-risk susceptibility gene whose expression is significantly reduced in AD patients. Studies have shown that SORL1 mainly plays a role in the early endosome and trans-Golgi, and affects the transport and metabolism of β-amyloid precursor protein by interacting with different cytoplasmic adapters, and then participates in the occurrence and development of AD. In addition, SORL1 gene knockout resulted in learning and memory impairment, abnormal distribution of n-methyl-D-aspartate receptor expression, and decreased expression of brain-derived neurotrophic factor and synaptic related proteins. It is suggested that SORL1 is involved in the pathogenesis of AD by regulating the signal axis of N-methyl-D-aspartate receptor-adenosine cyclophosphate-effecting-element binding protein (CREB) -brain-derived neurotrophic factor.

Bioapplications of SORL1

Recombinant SORL1 protein can be used to study its functions in intracellular material transport, immune response, cell adhesion and cell migration, especially in the study of Alzheimer's disease (AD), to explore how SORL1 affects the transport and metabolism of β-amyloid precursor protein (APP) and its role in the development of the disease. The development of drugs or antibodies that target SORL1 may provide new strategies for the treatment of certain diseases, especially in the field of AD therapy.