HAPLN2

Official Full Name

hyaluronan and proteoglycan link protein 2

Organism

Homo sapiens

GeneID

60484

Background

Predicted to enable hyaluronic acid binding activity. Predicted to be involved in nervous system development; positive regulation of neuroblast proliferation; and skeletal system development. Predicted to act upstream of or within establishment of blood-nerve barrier and extracellular matrix assembly. Predicted to be located in extracellular matrix. Predicted to be active in extracellular space; perineuronal net; and synapse. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

BRAL1;

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Detailed Information

Recent Research Progress

The human HAPLN2 is encoded by four exons, consisting of one immunoglobulin (Ig) fold and two proteoglycan tandem repeat (PTR) domains. Some researches have showed that Hapln2 mRNA was detected solely in the adult human and mouse brains. Furthermore, some researches have revealed that the expression of Hapln2 started at P20 in mice, as axonal myelination took place in the white matter and was predominantly expressed in myelinated fiber tracts in the adult brain. Hapln2, one of the hyaluronan and proteoglycan binding link proteins family, redominantly expressed in myelinated fiber tracts in the adult brain, has been reported to play an important role in maintaining and enhancing extracellular matrix (ECM) structures and function, which is in the formation of diffusion barrier around the nodes of Ranvier and conduction velocity in mouse brain. Hapln2 was co-localized with versican at the nodes of Ranvier in the myelinated white.

More and more evidences indicated that Hapln2 is interestingly associated with brain disorders. Previous results have showed that Hapln2-deficient mice exhibited abnormal expression pattern of hyaluronan-associated ECM and decrease of nerve conduction speed in the brain, indicating the vital role of Hapln2 for neuronal conductivity. What’s more, the Hapln2 expression levels were remarkably reduced in schizophrenia anterior temporal lobe, while Hapln2 has been recently shown to be accumulated in the neurofibrillary tangle of Alzheimer’s brain.

In particular, elevated Hapln2 expression contributes to protein aggregation and neurodegeneration in Parkinson’s Disease. Wang Qinqin et al., who found that hyaluronic acid and proteoglycan binding protein 2 (Hapln2) is one of the differentially expressed proteins in the substantia nigra tissue of PD patients and healthy control subjects in a previous quantitative proteomics study, further studied the potential role of Hapln2 in the pathogenesis of PD. They characterized the expression pattern of Hapln2. In situ hybridization revealed that Hapln2 mRNA was widely expressed in adult rat brain with high abundance in the substantia nigra. Immunoblotting showed that expression levels of Hapln2 were markedly upregulated in the substantia nigra of either human subjects with Parkinson’s disease compared with healthy control. Likewise, there were profound increases in Hapln2 expression in neurotoxin 6-hydroxydopamine-treated rat. Over-expression of Hapln2 in vitro increased vulnerability of MES23.5 cells, a dopaminergic cell line, to 6-hydroxydopamine. Moreover, Hapln2 over-expression led to the formation of cytoplasmic aggregates which were co-localized with ubiquitin and E3 ligases including Parkin, Gp78, and Hrd1 in vitro. Endogenous α-synuclein was also localized in Hapln2-containing aggregates and ablation of Hapln2 led to a marked decrease of α-synuclein in insoluble fraction compared with control. In other words, Hapln2 is identified as a novel factor contributing to neurodegeneration in PD. Surprisingly, Hapln2 ablation led to a significant increase of the proportion of insoluble form of α-synuclein in mouse brain. Hapln2 is involved in PD pathogenesis and the role of Hapln2 in PD may be associated with ubiquitin-proteasome pathway (UPP).

Interestingly, some research has indicated that HAPLN4 and HAPLN2 are the predominant members of this family in the adult human brain but are strongly reduced in the tumor parenchyma. In the study of the effects of cell adhesion molecules on the survival of ovarian cancer, Ping-Ying Chang et al. showed that highly methylation of HAPLN2 were significantly associated with poor progression-free survival of ovarian cancer. There may be some other close links between HAPLN2 and tumor, which need to be further examined yet.

References:

Qinqin Wang, et al. Elevated Hapln2 Expression Contributes to Protein Aggregation and Neurodegeneration in an Animal Model of Parkinson’s Disease. Frontiers in Aging Neuroscience, 2016, 8.
Bandopadhyay R. Sequential Extraction of Soluble and Insoluble Alpha-Synuclein from Parkinsonian Brains. Journal of Visualized Experiments Jove, 2016(107).
Ping-Ying Chang, et al. An epigenetic signature of adhesion molecules predicts poor prognosis of ovarian cancer patients. Oncotarget, 2017, 8(32):53432-53449.

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