Hapln2, also known as hyaluronan and proteoglycan link protein 2, is crucial for the binding of chondroitin sulfate proteoglycans to hyaluronan. It is involved in maintaining the extracellular matrix (ECM) integrity, and its function is essential for normal neuronal conductivity [1,5]. Hapln2-related genes are part of a gene family physically linked adjacent to chondroitin sulfate proteoglycan core protein genes, suggesting coordinated expression and importance in tissue architecture and function [5].

Hapln2 deficiency leads to abnormal ECM protein expression and neuronal conductivity dysfunction [1]. In Parkinson's disease (PD), studies on animal models have shown that Hapln2 promotes α-synuclein aggregation, contributing to neurodegeneration. Overexpression of Hapln2 in dopaminergic cell lines increases their vulnerability to neurotoxins, and cytoplasmic aggregates co-localize with ubiquitin and E3 ligases. Ablation of Hapln2 reduces α-synuclein in the insoluble fraction [2]. Also, in aging mouse brains, Hapln2, which promotes α-synuclein aggregation in PD patients, shows increased abundance [3]. In the context of stroke, proteome analysis in mice indicates ischemia-induced overexpression of Hapln2, more pronounced in aged post-ischemic animals [4]. In temporal lobe epilepsy, Hapln2 has been identified as one of the Hub genes through combined transcriptomics and proteomics analysis for potential biomarker screening in the acute phase [6].

In summary, Hapln2 is essential for maintaining normal neuronal function, especially in the context of the extracellular matrix and nerve conduction. Studies using gene-modified models, such as those with Hapln2 ablation, have revealed its significant role in neurodegenerative diseases like PD, as well as in stroke and temporal lobe epilepsy, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Wang, Qinqin, Wang, Chunmei, Ji, Bingyuan, Yang, Chunqing, Chen, Jing. 2019. Hapln2 in Neurological Diseases and Its Potential as Therapeutic Target. In Frontiers in aging neuroscience, 11, 60. doi:10.3389/fnagi.2019.00060. https://pubmed.ncbi.nlm.nih.gov/30949044/

2. Wang, Qinqin, Zhou, Qinbo, Zhang, Shuzhen, Gu, Xiaosong, Zhou, Jiawei. 2016. Elevated Hapln2 Expression Contributes to Protein Aggregation and Neurodegeneration in an Animal Model of Parkinson's Disease. In Frontiers in aging neuroscience, 8, 197. doi:10.3389/fnagi.2016.00197. https://pubmed.ncbi.nlm.nih.gov/27601993/

3. Mohallem, Rodrigo, Schaser, Allison J, Aryal, Uma K. 2024. Molecular Signatures of Neurodegenerative Diseases Identified by Proteomic and Phosphoproteomic Analyses in Aging Mouse Brain. In Molecular & cellular proteomics : MCP, 23, 100819. doi:10.1016/j.mcpro.2024.100819. https://pubmed.ncbi.nlm.nih.gov/39069073/

4. Chmelova, Martina, Androvic, Peter, Kirdajova, Denisa, Anderova, Miroslava, Vargova, Lydia. 2023. A view of the genetic and proteomic profile of extracellular matrix molecules in aging and stroke. In Frontiers in cellular neuroscience, 17, 1296455. doi:10.3389/fncel.2023.1296455. https://pubmed.ncbi.nlm.nih.gov/38107409/

5. Spicer, Andrew P, Joo, Adriane, Bowling, Rodney A. 2003. A hyaluronan binding link protein gene family whose members are physically linked adjacent to chondroitin sulfate proteoglycan core protein genes: the missing links. In The Journal of biological chemistry, 278, 21083-91. doi:. https://pubmed.ncbi.nlm.nih.gov/12663660/

6. Huang, Cong, You, Zhipeng, He, Yijie, Liu, Xingan, Sun, Jiahang. 2023. Combined transcriptomics and proteomics forecast analysis for potential biomarker in the acute phase of temporal lobe epilepsy. In Frontiers in neuroscience, 17, 1145805. doi:10.3389/fnins.2023.1145805. https://pubmed.ncbi.nlm.nih.gov/37065920/