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Acta Neuropathol Commun ; 8(1): 220, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33308320

RESUMO

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.


Assuntos
Encéfalo/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Ácido Linoleico/farmacologia , Mitocôndrias/efeitos dos fármacos , Doença de Parkinson/fisiopatologia , Equilíbrio Postural/efeitos dos fármacos , Ácido alfa-Linolênico/farmacologia , Animais , Transporte Axonal/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Deutério , Humanos , Inflamação , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/genética , Doença de Parkinson/patologia , Ratos , Ratos Transgênicos , Substância Negra , alfa-Sinucleína/genética
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