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Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α-Synucleinopathy
Assylbek Zhylkibayev1, Christopher R Starr2, M Iqbal Hossain3
1Department of Biochemistry, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.
Abstract:
This study investigated the therapeutic potential of the nuclear retinoid X receptor (RXR) in mitigating the progression of alpha-synucleinopathies (αSNPs), particularly in Parkinson's disease (PD). PD-like pathology in mice was successfully induced through the co-delivery of AAV expressing human α-synuclein (αS) and αS preformed fibrils (PFFs) into the substantia nigra pars compacta (SNpc). Significant increases in Lewy body (LB)-like inclusions, loss of tyrosine hydroxylase-positive (TH+) neurons, and reductions in dopamine (DA) levels in the striatum were observed. Additionally, diminished levels of PPARα and NURR1-proteins essential for neuronal survival-along with elevated expression of IBA1 and GFAP, markers of microglial activation and astrocytic gliosis, respectively, are associated with the pathogenesis of Parkinson's disease. AAV-mediated overexpression of human RXRα demonstrated preservation of TH+ neurons, prevention of DA decline, and attenuation of αS accumulation. Furthermore, RXR-treated PD brains showed a reduced number of GFAP+ and Iba1+ cells, decreased GFAP+ and IBA1+ immunoreactivity, and fewer and less widespread LB-like aggregates. RXR overexpression also enhanced the production of PPARα and NURR1. These findings suggest that RXRα upregulation promotes neuroprotection by mitigating αSNPs and chronic neuroinflammation, a major contributor to PD progression. This research underscores the therapeutic potential of targeting nuclear receptors, such as RXR, in neurodegenerative diseases like PD.
Insights
Nuclear Retinoid X Receptor (RXR) shows therapeutic potential for Parkinson's disease (PD) by reducing alpha-synuclein pathology and neuroinflammation. RXR upregulation protected neurons and preserved dopamine levels in a PD mouse model.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Alpha-synucleinopathies (αSNPs), like Parkinson's disease (PD), involve protein aggregation and neuroinflammation.
- Nuclear receptors, including Retinoid X Receptor (RXR), play roles in cellular health and disease.
- Current treatments for PD primarily manage symptoms, highlighting the need for disease-modifying therapies.
Purpose of the Study:
- To investigate the therapeutic efficacy of nuclear Retinoid X Receptor (RXR) in mitigating alpha-synucleinopathies (αSNPs) relevant to Parkinson's disease (PD).
- To explore RXR's potential to counteract neuroinflammation and neuronal loss associated with PD pathogenesis.
Main Methods:
- Induced PD-like pathology in mice using adeno-associated virus (AAV) vectors expressing human alpha-synuclein (αS) and pre-formed fibrils (PFFs) in the substantia nigra pars compacta (SNpc).
- Administered AAV-mediated overexpression of human RXRα in the PD mouse model.
- Assessed neuroprotection by quantifying tyrosine hydroxylase-positive (TH+) neurons, dopamine (DA) levels, alpha-synuclein (αS) accumulation, Lewy body (LB)-like inclusions, and markers of microglial activation (IBA1) and astrocytic gliosis (GFAP).
- Measured levels of neuroprotective proteins PPARα and NURR1.
Main Results:
- PD model exhibited increased LB-like inclusions, TH+ neuron loss, and reduced striatal DA levels.
- RXRα overexpression preserved TH+ neurons, prevented DA decline, and attenuated αS accumulation.
- RXR treatment reduced GFAP+ and Iba1+ cells, decreased associated immunoreactivity, and lessened LB-like aggregates.
- RXR upregulation enhanced PPARα and NURR1 protein levels.
Conclusions:
- Upregulation of RXRα demonstrates significant neuroprotective effects against αSNPs and associated neuroinflammation in a PD model.
- Targeting nuclear receptors like RXR offers a promising therapeutic strategy for neurodegenerative diseases such as Parkinson's disease.
- RXR activation mitigates key pathological hallmarks of PD, including protein aggregation, neuronal loss, and neuroinflammation.
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