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1.
Proc Natl Acad Sci U S A ; 118(31)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34326260

RESUMO

Loss-of-function mutations in acid beta-glucosidase 1 (GBA1) are among the strongest genetic risk factors for Lewy body disorders such as Parkinson's disease (PD) and Lewy body dementia (DLB). Altered lipid metabolism in PD patient-derived neurons, carrying either GBA1 or PD αS mutations, can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) equilibrium toward aggregation-prone monomers. A resultant increase in pSer129+ αS monomers provides a likely building block for αS aggregates. 3K αS mice, representing a neuropathological amplification of the E46K PD-causing mutation, have decreased αS T:M ratios and vesicle-rich αS+ aggregates in neurons, accompanied by a striking PD-like motor syndrome. We asked whether enhancing glucocerebrosidase (GCase) expression could benefit αS dyshomeostasis by delivering an adeno-associated virus (AAV)-human wild-type (wt) GBA1 vector into the brains of 3K neonates. Intracerebroventricular AAV-wtGBA1 at postnatal day 1 resulted in prominent forebrain neuronal GCase expression, sustained through 6 mo. GBA1 attenuated behavioral deficits both in working memory and fine motor performance tasks. Furthermore, wtGBA1 increased αS solubility and the T:M ratio in both 3K-GBA mice and control littermates and reduced pS129+ and lipid-rich aggregates in 3K-GBA. We observed GCase distribution in more finely dispersed lysosomes, in which there was increased GCase activity, lysosomal cathepsin D and B maturation, decreased perilipin-stabilized lipid droplets, and a normalized TFEB translocation to the nucleus, all indicative of improved lysosomal function and lipid turnover. Therefore, a prolonged increase of the αS T:M ratio by elevating GCase activity reduced the lipid- and vesicle-rich aggregates and ameliorated PD-like phenotypes in mice, further supporting lipid modulating therapies in PD.


Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Glucosilceramidase/metabolismo , alfa-Sinucleína/metabolismo , Animais , Animais Recém-Nascidos , Glucosilceramidase/genética , Metabolismo dos Lipídeos , Lipídeos/química , Aprendizagem em Labirinto , Camundongos , Atividade Motora , Proteínas Recombinantes , alfa-Sinucleína/química
2.
NPJ Parkinsons Dis ; 10(1): 47, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38424059

RESUMO

Mutations in the α-Synuclein (αS) gene promote αS monomer aggregation that causes neurodegeneration in familial Parkinson's disease (fPD). However, most mouse models expressing single-mutant αS transgenes develop neuronal aggregates very slowly, and few have dopaminergic cell loss, both key characteristics of PD. To accelerate neurotoxic aggregation, we previously generated fPD αS E46K mutant mice with rationally designed triple mutations based on the α-helical repeat motif structure of αS (fPD E46K→3 K). The 3 K variant increased αS membrane association and decreased the physiological tetramer:monomer ratio, causing lipid- and vesicle-rich inclusions and robust tremor-predominant, L-DOPA responsive PD-like phenotypes. Here, we applied an analogous approach to the G51D fPD mutation and its rational amplification (G51D → 3D) to generate mutant mice. In contrast to 3 K mice, G51D and 3D mice accumulate monomers almost exclusively in the cytosol while also showing decreased αS tetramer:monomer ratios. Both 1D and 3D mutant mice gradually accumulate insoluble, higher-molecular weight αS oligomers. Round αS neuronal deposits at 12 mos immunolabel for ubiquitin and pSer129 αS, with limited proteinase K resistance. Both 1D and 3D mice undergo loss of striatal TH+ fibers and midbrain dopaminergic neurons by 12 mos and a bradykinesia responsive to L-DOPA. The 3D αS mice have decreased tetramer:monomer equilibria and recapitulate major features of PD. These fPD G51D and 3D mutant mice should be useful models to study neuronal αS-toxicity associated with bradykinetic motor phenotypes.

3.
Sci Adv ; 9(46): eadj1454, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37976363

RESUMO

Parkinson's disease (PD) is characterized by conversion of soluble α-synuclein (αS) into intraneuronal aggregates and degeneration of neurons and neuronal processes. Indications that women with early-stage PD display milder neurodegenerative features suggest that female sex partially protects against αS pathology. We previously reported that female sex and estradiol improved αS homeostasis and PD-like phenotypes in E46K-amplified (3K) αS mice. Here, we aimed to further dissect mechanisms that drive this sex dimorphism early in disease. We observed that synaptic abnormalities were delayed in females and improved by estradiol, mediated by local estrogen receptor alpha (ERα). Aberrant ERα distribution in 3K compared to wild-type mice was paired with its decreased palmitoylation. Treatment with ML348, a de-palmitoylation inhibitor, increased ERα availability and soluble αS homeostasis, ameliorating synaptic plasticity and cognitive and motor phenotypes. Our finding that sex differences in early-disease αS-induced synaptic impairment in 3KL mice are in part mediated by palmitoylated ERα may have functional and pathogenic implications for clinical PD.


Assuntos
Doença de Parkinson , Sinucleinopatias , Animais , Feminino , Humanos , Masculino , Camundongos , Modelos Animais de Doenças , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Hipocampo/patologia , Lipoilação , Camundongos Transgênicos , Doença de Parkinson/genética
4.
Neurotherapeutics ; 19(3): 1018-1036, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35445353

RESUMO

Increasing evidence has shown that Parkinson's disease (PD) impairs midbrain dopaminergic, cortical and other neuronal subtypes in large part due to the build-up of lipid- and vesicle-rich α-synuclein (αSyn) cytotoxic inclusions. We previously identified stearoyl-CoA desaturase (SCD) as a potential therapeutic target for synucleinopathies. A brain-penetrant SCD inhibitor, YTX-7739, was developed and has entered Phase 1 clinical trials. Here, we report the efficacy of YTX-7739 in reversing pathological αSyn phenotypes in various in vitro and in vivo PD models. In cell-based assays, YTX-7739 decreased αSyn-mediated neuronal death, reversed the abnormal membrane interaction of amplified E46K ("3K") αSyn, and prevented pathological phenotypes in A53T and αSyn triplication patient-derived neurospheres, including dysregulated fatty acid profiles and pS129 αSyn accumulation. In 3K PD-like mice, YTX-7739 crossed the blood-brain barrier, decreased unsaturated fatty acids, and prevented progressive motor deficits. Both YTX-7739 treatment and decreasing SCD activity through deletion of one copy of the SCD1 gene (SKO) restored the physiological αSyn tetramer-to-monomer ratio, dopaminergic integrity, and neuronal survival in 3K αSyn mice. YTX-7739 efficiently reduced pS129 + and PK-resistant αSyn in both human wild-type αSyn and 3K mutant mice similar to the level of 3K-SKO. Together, these data provide further validation of SCD as a PD therapeutic target and YTX-7739 as a clinical candidate for treating human α-synucleinopathies.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Animais , Encéfalo/metabolismo , Humanos , Camundongos , Neurônios/metabolismo , Doença de Parkinson/genética , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
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