Background: ␣Syn toxicity is triggered by oligomerization of ␣Syn, and its formation is partly regulated by PUFAs. Results: MPTP-induced neurotoxicity and ␣Syn oligomerization are attenuated in Fabp3 Ϫ/Ϫ mice. Conclusion:FABP3 is implicated in arachidonic acid-induced ␣Syn oligomerization and promotes dopaminergic cell death. Significance: FABP3 aggravates MPTP-induced neuronal toxicity and ␣Syn accumulation.␣-Synuclein (␣Syn) accumulation in dopaminergic (DA) neurons is partly regulated by long-chain polyunsaturated fatty acids. We found that fatty acid-binding protein 3 (FABP3, H-FABP), a factor critical for arachidonic acid (AA) transport and metabolism in brain, is highly expressed in DA neurons. Fabp3 knock-out (Fabp3؊/؊ ) mice were resistant to 1-methyl-1,2,3,6-tetrahydropiridine-induced DA neurodegeneration in the substantia nigra pars compacta and showed improved motor function. Interestingly, FABP3 interacted with ␣Syn in the substantia nigra pars compacta, and ␣Syn accumulation following 1-methyl-1,2,3,6-tetrahydropiridine treatment was attenuated in Fabp3 ؊/؊ compared with wild-type mice. We confirmed that FABP3 overexpression aggravates AA-induced ␣Syn oligomerization and promotes cell death in PC12 cells, whereas overexpression of a mutant form of FABP3 lacking fatty-acid binding capacity did not. Taken together, ␣Syn oligomerization in DA neurons is likely aggravated by AA through FABP3 in Parkinson disease pathology.Parkinson disease (PD) 2 is a common motor disorder affecting Ͼ1% of the population over 65 years of age worldwide (1). Histopathologic features of PD are the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of cytoplasmic protein aggregates, known as Lewy bodies (LBs) (2). ␣-Synuclein (␣Syn), a 140-amino acid protein, is associated with synaptic vesicles in presynaptic nerve terminals (3), and ␤-sheet fibrillar aggregates, including ␣Syn, are major components of LBs. ␣Syn accumulation is associated with progressive loss of DA neurons, implicating that activity in PD pathogenesis (4). In addition, duplication/triplication (5-7) and missense mutations (A53T, A30P, E46K, H50Q, and G51D) (8 -12) in the ␣Syn gene SNCA are linked to familial early onset PD, suggesting that the mutations accelerate ␣Syn aggregation and disease progression.␣Syn toxicity is triggered by oligomerization of ␣Syn in vitro (13) and in vivo (14), indicating that oligomerization underlies cytotoxic events in PD. However, mechanisms underlying ␣Syn oligomerization in DA neurons are unclear. Previous reports suggested that ␣Syn binds fatty acids, particularly long-chain polyunsaturated fatty acids (PUFAs) (15,16), and that ␣Syn oligomerization and the appearance of LB-like inclusions in cultured mesencephalic neuronal cells are enhanced by exposure to . In addition, abnormally high PUFA levels are observed in ␣Syn-transfected mesencephalic neuronal cells and in PD brains, whereas lower levels are seen in mice lacking ␣Syn (17, 18), suggesting that PUFA binding to ␣Syn is ...

Fragile X-related tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by CGG triplet repeat expansions in FMR1, which elicit repeat-associated non-AUG (RAN) translation and produce the toxic protein FMRpolyG. We show that FMRpolyG interacts with pathogenic CGG repeat-derived RNA G-quadruplexes (CGG-G4RNA), propagates cell to cell, and induces neuronal dysfunction. The FMRpolyG polyglycine domain has a prion-like property, preferentially binding to CGG-G4RNA. Treatment with 5-aminolevulinic acid, which is metabolized to protoporphyrin IX, inhibited RAN translation of FMRpolyG and CGG-G4RNA–induced FMRpolyG aggregation, ameliorating aberrant synaptic plasticity and behavior in FXTAS model mice. Thus, we present a novel therapeutic strategy to target G4RNA prionoids.

Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX, which encodes a chromatin-remodeling protein. Genome-wide analyses in mouse and human cells indicate that ATRX tends to bind to G-rich sequences with a high potential to form G-quadruplexes. Here, we report that Atrx mutation induces aberrant upregulation of Xlr3b expression in the mouse brain, an outcome associated with neuronal pathogenesis displayed by ATR-X model mice. We show that ATRX normally binds to G-quadruplexes in CpG islands of the imprinted Xlr3b gene, regulating its expression by recruiting DNA methyltransferases. Xlr3b binds to dendritic mRNAs, and its overexpression inhibits dendritic transport of the mRNA encoding CaMKII-α, promoting synaptic dysfunction. Notably, treatment with 5-ALA, which is converted into G-quadruplex-binding metabolites, reduces RNA polymerase II recruitment and represses Xlr3b transcription in ATR-X model mice. 5-ALA treatment also rescues decreased synaptic plasticity and cognitive deficits seen in ATR-X model mice. Our findings suggest a potential therapeutic strategy to target G-quadruplexes and decrease cognitive impairment associated with ATR-X syndrome.

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