Iroquois Homeobox Protein 2 Identified as a Potential Biomarker for Parkinson's Disease.

Hyuna Sim,Sunwha Cho,Hee Min Yoo,Hana Lee,Jisun Kim,Janghwan Kim,Aruem Baek,Joo-Eun Lee,Hyemyung Seo,Young-Joo Jeon,Mi-Na Kweon,Hyung Gun Kim,Mi-Young Son

doi:10.3390/ijms21103455

Abstract

The diagnosis of Parkinson’s disease (PD) is initiated after the occurrence of motor symptoms, such as resting tremors, rigidity, and bradykinesia. According to previous reports, non-motor symptoms, notably gastrointestinal dysfunction, could potentially be early biomarkers in PD patients as such symptoms occur earlier than motor symptoms. However, connecting PD to the intestine is methodologically challenging. Thus, we generated in vitro human intestinal organoids from PD patients and ex vivo mouse small intestinal organoids from aged transgenic mice. Both intestinal organoids (IOs) contained the human LRRK2 G2019S mutation, which is the most frequent genetic cause of familial and sporadic PD. By conducting comprehensive genomic comparisons with these two types of IOs, we determined that a particular gene, namely, Iroquois homeobox protein 2 (IRX2), showed PD-related expression patterns not only in human pluripotent stem cell (PSC)-derived neuroectodermal spheres but also in human PSC-derived neuronal cells containing dopaminergic neurons. We expected that our approach of using various cell types presented a novel technical method for studying the effects of multi-organs in PD pathophysiology as well as for the development of diagnostic markers for PD.

Highlights

Parkinson’s disease (PD) is a common and complex neurodegenerative disorder that results from the progressive loss of midbrain dopaminergic neurons in the substantia nigra (SN)
We observed the comprehensive molecular changes caused by the leucine-rich repeat kinase 2 (LRRK2) Gly2019Ser substitution (G2019S) mutation in neural and intestinal 3D culture model systems based on the same PD-specific pluripotent stem cell (PSC) [17]
One of the most interesting aspects of the results was that the gene expression difference was more distinct in human intestinal organoids than in human neuroectodermal spheres, even though PD is a well-known neurodegenerative disorder

Summary

Introduction

Parkinson’s disease (PD) is a common and complex neurodegenerative disorder that results from the progressive loss of midbrain dopaminergic neurons in the substantia nigra (SN). Typical motor symptoms occur when up to 60% of the dopaminergic neurons of the SN have already degenerated [5] It is, essential to develop an early diagnosis marker for the successful treatment for PD. The onset of motor symptoms can be preceded by a premotor or prodromal phase characterized by specific non-motor symptoms [6]. These include emotional problems, cognitive dysfunction, sleep disturbances, sensory manipulation, as well as autonomic dysregulations [7]. The pathogenic accumulation of phosphorylated alpha-synuclein protein, the neuropathological hallmark of PD, in the bowel can occur during the early stages of the disease, prior to the onset of motor symptoms [11]. The risk of PD was lower in patients who underwent truncal vagotomy, which indicates the linkage between the brain and the GI tract is influential in the development of PD [12,13]

Methods

Results

Conclusion