Abstract
Parkinson’s disease (PD) is a movement disorder caused by progressive degeneration of the midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SNc). Despite intense research efforts over the past decades, the etiology of PD remains largely unknown. Here, we discovered the involvement of trophoblast glycoprotein (Tpbg) in the development of PD-like phenotypes in mice. Tpbg expression was detected in the ventral midbrain during embryonic development and in mDA neurons in adulthood. Genetic ablation of Tpbg resulted in mild degeneration of mDA neurons in aged mice (12–14 months) with behavioral deficits reminiscent of PD symptoms. Through in silico analysis, we predicted potential TPBG-interacting partners whose functions were relevant to PD pathogenesis; this result was substantiated by transcriptomic analysis of the SNc of aged Tpbg knockout mice. These findings suggest that Tpbg is a new candidate gene associated with PD and provide a new insight into PD pathogenesis.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting approximately 1% of the population aged above 65 years
At E11.5, the sagittal sections of the developing mouse brain highlighted enhanced green fluorescent protein (EGFP) expression throughout the rostro-caudal axis of the ventral midbrain (VM). This expression pattern overlapped with immunoreactivity to LMX1A and FOXA2, specific markers for midbrain dopaminergic (mDA) precursors and floor plate (FP), respectively, suggesting that trophoblast glycoprotein (Tpbg)-expressing cells are a subset of mDA neuron progenitors (Fig. 1b)
EGFP+ cells were initially concentrated at the medial part of the ventral midline, and they overlapped with FOXA2- and LMX1A-expressing mDA domains through the length of the VM at E11.5 and E12.5 (Fig. 1c)
Summary
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting approximately 1% of the population aged above 65 years. Accumulating evidence suggests that the pathological form of α-SYN might trigger neuroinflammation through microglial activation, contributing to the apoptotic death of dopaminergic neurons[4,5]. Most PD occurrences are idiopathic; the identification of genetic factors that cause inheritable forms of PD has yielded crucial insights into possible pathogenic mechanisms. Despite extensive research conducted in this area, only a few genes are known to be directly involved in monogenic forms of PD, and 90 genetic variants identified by meta-analysis of genome-wide association studies accounts for 16−36% of the risk of idiopathic PD depending on prevalence[9]
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