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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Food-borne -fatty acids (TFAs) are mainly produced as byproducts during food manufacture. Recent epidemiological studies have revealed that TFA consumption is a major risk factor for various disorders, including atherosclerosis. However, the underlying mechanisms in this disease etiology are largely unknown. Here we have shown that TFAs potentiate activation of apoptosis signal-regulating kinase 1 (ASK1) induced by extracellular ATP, a damage-associated molecular pattern leaked from injured cells. Major food-associated TFAs such as elaidic acid (EA), linoelaidic acid, and -vaccenic acid, but not their corresponding isomers, dramatically enhanced extracellular ATP-induced apoptosis, accompanied by elevated activation of the ASK1-p38 pathway in a macrophage-like cell line, RAW264.7. Moreover, knocking out the ASK1-encoding gene abolished EA-mediated enhancement of apoptosis. We have reported previously that extracellular ATP induces apoptosis through the ASK1-p38 pathway activated by reactive oxygen species generated downstream of the P2X purinoceptor 7 (P2X). However, here we show that EA did not increase ATP-induced reactive oxygen species generation but, rather, augmented the effects of calcium/calmodulin-dependent kinase II-dependent ASK1 activation. These results demonstrate that TFAs promote extracellular ATP-induced apoptosis by targeting ASK1 and indicate novel TFA-associated pathways leading to inflammatory signal transduction and cell death that underlie the pathogenesis and progression of TFA-induced atherosclerosis. Our study thus provides insight into the pathogenic mechanisms of and proposes potential therapeutic targets for these TFA-related disorders.

J. Neurochem. (2012) 120, 541–551. Abstract Parkinson’s disease (PD) patients frequently reveal deficit in cognitive functions during the early stage in PD. The dopaminergic neurotoxin, MPTP‐induced neurodegeneration causes an injury of the basal ganglia and is associated with PD‐like behaviors. In this study, we demonstrated that deficits in cognitive functions in MPTP‐treated mice were associated with reduced calcium/calmodulin‐dependent protein kinase II (CaMKII) autophosphorylation and impaired long‐term potentiation (LTP) induction in the hippocampal CA1 region. Mice were injected once a day for 5 days with MPTP (25 mg/kg i.p.). The impaired motor coordination was observed 1 or 2 week after MPTP treatment as assessed by rota‐rod and beam‐walking tasks. In immunoblotting analyses, the levels of tyrosine hydroxylase protein and CaMKII autophosphorylation in the striatum were significantly decreased 1 week after MPTP treatment. By contrast, deficits of cognitive functions were observed 3–4 weeks after MPTP treatment as assessed by novel object recognition and passive avoidance tasks but not Y‐maze task. Impaired LTP in the hippocampal CA1 region was also observed in MPTP‐treated mice. Concomitant with impaired LTP induction, CaMKII autophosphorylation was significantly decreased 3 weeks after MPTP treatment in the hippocampal CA1 region. Finally, the reduced CaMKII autophosphorylation was closely associated with reduced AMPA‐type glutamate receptor subunit 1 (GluR1; Ser‐831) phosphorylation in the hippocampal CA1 region of MPTP‐treated mice. Taken together, decreased CaMKII activity with concomitant impaired LTP induction in the hippocampus likely account for the learning disability observed in MPTP‐treated mice.

Oligomerization and/or aggregation of α-synuclein (α-Syn) triggers α-synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies. It is known that α-Syn can spread in the brain like prions; however, the mechanism remains unclear. We demonstrated that fatty acid binding protein 3 (FABP3) promotes propagation of α-Syn in mouse brain. Animals were injected with mouse or human α-Syn pre-formed fibrils (PFF) into the bilateral substantia nigra pars compacta (SNpc). Two weeks after injection of mouse α-Syn PFF, wild-type (WT) mice exhibited motor and cognitive deficits, whereas FABP3 knock-out (Fabp3−/−) mice did not. The number of phosphorylated α-Syn (Ser-129)-positive cells was significantly decreased in Fabp3−/− mouse brain compared to that in WT mice. The SNpc was unilaterally infected with AAV-GFP/FABP3 in Fabp3−/− mice to confirm the involvement of FABP3 in the development of α-Syn PFF toxicity. The number of tyrosine hydroxylase (TH)- and phosphorylated α-Syn (Ser-129)-positive cells following α-Syn PFF injection significantly decreased in Fabp3−/− mice and markedly increased by AAV-GFP/FABP3 infection. Finally, we confirmed that the novel FABP3 inhibitor MF1 significantly antagonized motor and cognitive impairments by preventing α-Syn spreading following α-Syn PFF injection. Overall, FABP3 enhances α-Syn spreading in the brain following α-Syn PFF injection, and the FABP3 ligand MF1 represents an attractive therapeutic candidate for α-synucleinopathy.