Inhibition of MPTP-induced α-synuclein oligomerization by fatty acid-binding protein 3 ligand in MPTP-treated mice

Abstract

&NA; Accumulation and aggregation of &agr;‐synuclein (&agr;Syn) triggers dopaminergic (DAergic) neuronal loss in Parkinson s disease (PD). This pathological event is partly facilitated by the presence of long‐chain polyunsaturated fatty acids (LC‐PUFAs), including arachidonic acid. The intracellular transport and metabolism of LC‐PUFAs are mediated by fatty acid‐binding proteins (FABPs). We previously reported that heart‐type FABP (FABP3) interacts with &agr;Syn, thereby promoting &agr;Syn oligomerization in DAergic neurons in the substantia nigra pars compacta (SNpc) following 1‐methyl‐1,2,3,6‐tetrahydropyridine (MPTP) treatment. This &agr;Syn oligomerization is prevented in Fabp3 gene knock out mice. We document a novel FABP3 ligand, MF1 (4‐(2‐(1‐(2‐chlorophenyl)‐5‐phenyl‐1H‐pyrazol‐3‐yl)phenoxy)butanoic acid), that inhibits &agr;Syn accumulation in DA neurons, thereby inhibiting the oligomerization of &agr;Syn, loss of DAergic neurons, and PD‐like motor deficits in MPTP‐treated mice. Chronic oral administration of MF1 (0.3 or 1.0 mg/kg/day) significantly improved motor impairments and inhibited MPTP‐induced accumulation and oligomerization of &agr;Syn in the SNpc, and in turn prevented loss of tyrosine hydroxylase (TH)‐positive cells in the SNpc. MF1 administration (0.1, 0.3, or 1.0 mg/kg/day) also restored MPTP‐induced cognitive impairments. Although chronic administration of l‐DOPA (3,4‐dihydroxl‐l‐phenylalanine; 25 mg/kg/day, i.p.) also improved motor deficits, it failed to improve the cognitive impairments. In addition, l‐DOPA failed to inhibit DAergic neuronal loss and &agr;Syn pathologies in the SNpc. In summary, the novel FABP3 ligand MF1 rescues MPTP‐induced behavioural and neuropathological features, suggesting that MF1 may be a disease‐modifying drug candidate for synucleinopathies. Highlights&agr;‐synuclein (&agr;Syn) triggers dopaminergic neuronal loss in Parkinson s disease.We report a FABP3 ligand, MF1 that inhibits &agr;Syn accumulation in MPTP‐treated mice.MF1 rescues MPTP‐induced behavioural and neuropathological features.MF1 may be a disease‐modifying drug candidate for synucleinopathies.