Abstract
α-Synuclein (α-syn) is a 140-amino acid protein, the physiological function of which has yet to be clarified. It is involved in several neurodegenerative disorders, and the interaction of the protein with brain lipids plays an important role in the pathogenesis of Parkinson’s disease (PD). Polyunsaturated fatty acids (PUFA) are highly abundant in the brain where they play critical roles in neuronal membrane fluidity and permeability, serve as energy reserves and function as second messengers in cell signaling. PUFA concentration and composition in the brain are altered with age when also an increase of lipid peroxidation is observed. Considering that PD is clearly correlated with oxidative stress, PUFA abundance and composition became of great interest in neurodegeneration studies because of PUFA’s high propensity to oxidize. The high levels of the PUFA docosahexaenoic acid (DHA) in brain areas containing α-syn inclusions in patients with PD further support the hypothesis of possible interactions between α-syn and DHA. Additionally, a possible functional role of α-syn in sequestering the early peroxidation products of fatty acids was recently proposed. Here, we provide an overview of the current knowledge regarding the molecular interactions between α-syn and fatty acids and the effect exerted by the protein on their oxidative state. We highlight recent findings supporting a neuroprotective role of the protein, linking α-syn, altered lipid composition in neurodegenerative disorders and PD development.
Highlights
Parkinson’s disease (PD) is a progressive, neurodegenerative disorder, characterized by severe motor symptoms, such as tremor, difficulty in movements and rigidity
The pathological distinctive elements of PD are represented by the Lewy bodies (LB) and Lewy neuritis (LN), ubiquinated protein inclusions mainly composed of the presynaptic protein α-synuclein (α-syn) [1]
Both in familial and in sporadic PD, the protein is present as an insoluble filamentous aggregate, known as a fibril, with specific morphology and structure, and α-syn dysfunction appears a critical determinant for the development of the disease [8]
Summary
Parkinson’s disease (PD) is a progressive, neurodegenerative disorder, characterized by severe motor symptoms, such as tremor, difficulty in movements and rigidity. In conditions of oxidative stress, as well as in patients affected by PD, the neuronal levels of PUFAs in a non-esterified form were found higher than normal [10] and, anyway, altered in various neurological disorder [11]. The levels of those PUFA-derived substances, representing the markers of oxidized lipids, were found to be ten-fold higher than normal in the substantia nigra of patients affected by PD [12]. We and other hypothesize that the protein/PUFA molecular ratio in neurons is a discriminant factor, and increases in the levels of either certain PUFAs or α-syn monomers in the cytoplasm can produce different effects in physiological and pathological conditions [13,14,15]. Studies of drugs targeting PUFAs are underway as a novel approach for the exaltation of their beneficial effects on neurodegeneration, but probably further investigations are required to clarify the implication of brain PUFAs in health and disease and the link with α-syn
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