HAPLN4

Official Full Name

hyaluronan and proteoglycan link protein 4

Organism

Homo sapiens

GeneID

404037

Background

Predicted to be a structural constituent of synapse-associated extracellular matrix. Predicted to be involved in several processes, including GABAergic synaptic transmission; nervous system development; and positive regulation of neuroblast proliferation. Predicted to be located in extracellular region. Predicted to be active in extracellular space; perineuronal net; and synapse. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

BRAL2;

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Detailed Information

Recent Research Progress

HAPLN4, also known as brain-specific link protein (Bral-2), can be find throughout the neurosensory retina, with strong labeling of the nerve fiber and ganglion cell layers. According to some researches, hapln4-brevican interaction may play a key role in synaptic stabilization and the structural integrity of the Perineuronal nets (PNNs). The absence of perineuronal net formation at the end of the developmental period in the bral-2-knockout mice results in higher hearing threshold at high frequencies and weaker temporal resolution ability in adult bral-2-knockout animals compared to WT mice. Besides, HAPLN4/Bral2 is indispensable for the proper localization of brevican and the structural integrity of the PNNs in the brainstem and cerebellum. Bral2 may have a role in the organization of the PNNs, in association with brevican, that is independent of aggrecan binding. There was a heterogenous attenuation of PNNs components, including glycosaminoglycans, indicating the elaborate molecular organization of the PNNs components. Furthermore, M. Blosa indicated the change of HaPLN4 expression can be used as a biological indicator for the direct interaction between ECM and synapse. There has been more and more evidences showed that HaPLN4 may play an important role in nervous system related diseases.

A recent research validated that HAPLN4 was a direct target of miR-19b. MiR-19b, has been reported to be involved in nervous system disease including Parkinson's disease (PD), suppressed HAPLN4 expression by binding to its 3’-UTR, the complementary sequences of miR-19b, in a posttranscriptional manner. HAPLN4 has been pointed to be restricted in expression to the brain/central nervous system and be implicated in multiple brain injury disease. In the present study, the results found that over-expression of HAPLN4 dramatically accelerated cell apoptosis of MPP+-treated SH-SY5Y cells which is a PD model in vitro. According to a previous research, Moreover, the restoration of HAPLN4 expression significantly reversed miR-19b-triggered anti-apoptosis effect in MPP+-induced SH-SY5Y cells. Considering the regulatory effects of miR-19b on HAPLN4 expression, the research concluded that HAPLN4 enhanced MPP+-induced apoptosis possibly via increasing caspase 3 activity, ROS production and inflammatory responses. A recent report demonstrated that HAPLN4 showed a high expression following an injury of the brain. Also, the mutations or variants of gene HAPLN4 was reported to be associated with the pathophysiological process of essential tremor (ET). HAPLN2 and HAPLN4 are he members of the hyaluronan and proteoglycan binding link proteins. Similar to HAPLN2, current study revealed that HAPLN4 activated MAPK signaling pathway via enhancing the phosphorylation levels of ERK, JNK and p38, and HAPLN4-triggered MAPK signaling was markedly reversed by regaining of miR-19b expression. All these data implied that miR-19b abated MPP+-induced injury of SHSY5Y cells by blocking MAPK signaling pathway through targeting HAPLN4. Taken together, the neuroprotective effect of miR-19b might be mediated by HAPLN4/MAPK pathway in SH-SY5Y cells.

Interestingly, Jonathan M. Heppner has revealed HAPLN4 may be associated with the pathogenesis of tardive osteoarthritis. What’s more, the analysis of a novel framework for differential co-expression networks, developed At the Department of Biotechnology and Food Science at the Norwegian University of Science and Technology (NTNU), have recently identified HAPLN4 with Possible rheumatoid arthritis(RA)-related functions.

References:

Wei Liu, et al. MiR-19b alleviates MPP+-induced neuronal cytotoxicity via targeting the HAPLN4/MAPK pathway in SH-SY5Y cells. Royal Society of Chemistry, 2018, 8, 10706-10714.
Liu X, et al. Identification of candidate genes for familial early-onset essential tremor. European Journal of Human Genetics, 2016, 24(7):1009-1015.
Heppner J M, et al. Extracellular matrix disruption is an early event in the pathogenesis of skeletal disease in mucopolysaccharidosis I. Molecular Genetics & Metabolism, 2015, 114(2):146-155.
Popelář J, et al. The absence of brain-specific link protein Bral2 in perineuronal nets hampers auditory temporal resolution and neural adaptation in mice. Physiological Research, 2017.

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