Abstract
Parkinson's disease (PD), the second most common age-associated progressive neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SN). The pathogenesis of PD and the mechanisms underlying the degeneration of DA neurons are still not fully understood. Our previous quantitative proteomics study revealed that hyaluronan and proteoglycan binding link protein 2 (Hapln2) is one of differentially expressed proteins in the substantia nigra tissues from PD patients and healthy control subjects. However, the potential role of Hapln2 in PD pathogenesis remains elusive. In the present study, we 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. Overexpression of Hapln2 in vitro increased vulnerability of MES23.5 cells, a dopaminergic cell line, to 6-hydroxydopamine. Moreover, Hapln2 overexpression 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. Thus, Hapln2 is identified as a novel factor contributing to neurodegeneration in PD. Our data provides new insights into the cellular mechanism underlying the pathogenesis in PD.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting more than 1% of the people aged over 65 years around the world (Delenclos et al, 2016)
It has been reported that the predicted open reading frame of hyaluronan and proteoglycan binding link protein 2 (Hapln2) encoded a polypeptide of 340 amino acids containing one immunoglobulin (Ig) fold and two proteoglycan tandem repeat (PTR) domains with an estimated molecular weight of 38 kDa (Hirakawa et al, 2000)
The same band was recognized by anti-GFP was more severe (GFP) antibody (Figure S1B), suggesting the anti-Hapln2 antibody is reliable for Western blotting
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting more than 1% of the people aged over 65 years around the world (Delenclos et al, 2016). It is mainly characterized by severe movement symptoms including resting tremor, slowness of movement, rigidity and postural instability (Kadoguchi et al, 2014; Delenclos et al, 2016). PD is marked by the progressive loss of dopaminergic (DA) neurons in the ventral midbrain and the formation of α-synucleincontaining aggregates in neuronal cell bodies and neuritis (Anderson et al, 2006; Kadoguchi et al, 2014). A large variety of possible pathogenic factors, including excessive release of oxygen free radicals during enzymatic dopamine breakdown, impairment of mitochondrial function and calcium homeostasis, dysregulation of LRRK2 kinase, neuroinflammation and loss of trophic support, have been reported to contribute to the disease processes, the etiology of PD has not yet been fully understood (Block and Hong, 2005; Dick et al, 2007; Paumier et al, 2015; Von Stockum et al, 2015), indicating the urgent need to identify target of PD pathogenesis
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