Abstract
Lipid peroxidation is a key to a portfolio of neurodegenerative diseases and plays a central role in α-synuclein (α-syn) toxicity, mitochondrial dysfunction and neuronal death, all key processes in the pathogenesis of Parkinson’s disease (PD). Polyunsaturated fatty acids (PUFAs) are important constituents of the synaptic and mitochondrial membranes and are often the first molecular targets attacked by reactive oxygen species (ROS). The rate-limiting step of the chain reaction of ROS-initiated PUFAs autoxidation involves hydrogen abstraction at bis-allylic sites, which can be slowed down if hydrogens are replaced with deuteriums. In this study, we show that targeted overexpression of human A53T α-syn using an AAV vector unilaterally in the rat substantia nigra reproduces some of pathological features seen in PD patients. Chronic dietary supplementation with deuterated PUFAs (D-PUFAs), specifically 0.8% D-linoleic and 0.3% H-linolenic, produced significant disease-modifying beneficial effects against α-syn-induced motor deficits, synaptic pathology, oxidative damage, mitochondrial dysfunction, disrupted trafficking along axons, inflammation and DA neuronal loss. These findings support the clinical evaluation of D-PUFAs as a neuroprotective therapy for PD.
Highlights
Age is the main risk factor for the development of neurodegenerative diseases, including Parkinson’s disease (PD), a severe neurological disorder characterized by the progressive and selective degeneration of dopamine (DA)-producing neurons in the substantia nigra (SN) and axonal projections [31]
In the first set of experiments, we examined whether D-Polyunsaturated fatty acids (PUFAs) could ameliorate an α-syn-associated motor phenotype resembling some aspects of PD (Fig. 1)
The displacement of the rat necessary to provoke a compensatory forelimb movement was significantly increased on the α-syn-exposed side relative to the GFPinjected side of rats treated with H-PUFAs (Fig. 1d)
Summary
Age is the main risk factor for the development of neurodegenerative diseases, including Parkinson’s disease (PD), a severe neurological disorder characterized by the progressive and selective degeneration of dopamine (DA)-producing neurons in the substantia nigra (SN) and axonal projections [31]. Lipid peroxidation (LPO) has been utilized as an indicator of reactive oxygen species (ROS)-mediated membrane phospholipid degradation, which directly affects cell membrane function. Beal et al acta neuropathol commun (2020) 8:220 outcome of LPO is the generation of a variety of reactive aldehyde species, such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE). The latter is the most cytotoxic end product and it is detected in neurofilament medium chains and it alters DA uptake, which links LPO to neuronal loss. Postmortem examination of PD brains showed an increased basal content of nigral MDA and the presence of 4-HNE-protein adducts in the SN DA neurons [54]. The concentration of F2-isoprostanes is significantly increased in the anterior cingulate cortex of PD subjects [1]
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