Female Sex and Brain-Selective Estrogen Benefit α-Synuclein Tetramerization and the PD-like Motor Syndrome in 3K Transgenic Mice

Abstract

Many studies report a higher risk for Parkinson's disease (PD) and younger age of onset in men. This, and the fact that the neuropathological process underlying PD symptoms may begin before menopause, suggests that estrogen-based hormone therapy could modify this higher risk in males. However, the effects of female sex or estrogen on ␣-synuclein (␣S) homeostasis and related PD neuropathology remain unknown. Here, we used an ␣S tetramer-abrogating mouse model of PD (3K) that amplifies the familial E46K PD mutation to investigate the effects of female sex and brain-selective estrogen treatment on ␣S tetramerization and solubility, formation of vesicle-rich ␣S ϩ aggregates, dopaminergic and cortical fiber integrity, and associated motor deficits. In male 3K mice, the motor phenotype became apparent at ϳ10 weeks and increased to age 6 months, paralleled by PD-like neuropathology, whereas 3K females showed a significant delay in onset. At 6 months, this beneficial phenotypic effect in 3K females was associated with a higher ␣S tetramer-to-monomer ratio and less decrease in dopaminergic and cortical fiber length and quantity. Brain-selective estrogen treatment in symptomatic 3K mice significantly increased the tetramer-to-monomer ratio, turnover by autophagy of aggregate-prone monomers, and neurite complexity of surviving DAergic and cortical neurons, in parallel with benefits in motor performance. Our findings support an upstream role for ␣S tetramer loss in PD phenotypes and a role for estrogen in mitigating PD-like neuropathology in vivo. Brain-selective estrogen therapy may be useful in delaying or reducing PD symptoms in men and postmenopausal women.

A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy

“…Thus far, DHED (Figure 3B) has been studied most extensively in preclinical animal models of E2-responsive maladies [23,36,50,51]. The unprecedented CNS selectivity of our approach in terms of prodrug bioactivation has also recently been confirmed independently from our laboratory [52,53]. We have also unambiguously shown the CNS-selective bioactivations of HEDD and αDHD to E1 and αE2, respectively [35,37].…”

A Stearoyl–Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α‐Synuclein Mice

“…The 3K mutation decreases the brain αS T:M ratio much more than overexpressing the human WT αS does, 10 and this is associated with gradually progressive motor deficits, including resting tremor and climbing, balance, and gait abnormalities, which typically begin at 3 months in males and become notably worse by age 6 months, as demonstrated by several timed motor tests, including pole climbing, 4-limb wire hanging, and rotarod walking. 10,22 We initially performed these tests at age 8 weeks to establish baseline motor performances, and we then randomly assigned WT and 3K αS tg mice matched for sex, age, and αS expression level to active 5b treatment (5b) or vehicle (Plb) groups (Fig 3).…”

“…22 Similar to PD, 23 there is a male preponderance in 3K mice in that females show less lowering of the αS T:M ratio and increased autophagic turnover of αS+ lipid-rich brain aggregates. 22 These multiple features make the 3K model highly suitable for the necessary preclinical testing of potentially disease-modifying approaches to PD.…”

“…Therefore, we have generated 3K αS transgenic (tg) mice and found their tetramer abrogation to accentuate the neuropathological and biochemical phenotypes of the WT or the familial (f) PD E46K (1K) αS mutation in an age-dependent manner. 10,22 The striking PD-like motor syndrome of 3K mice includes resting tremor, bradykinesia, rigidity, and gait deficits that respond in part to L-dopa treatment, while relatively subtle changes in forced gait patterns are observed in male WT αS-overexpressing mice versus their female counterparts. 22 Similar to PD, 23 there is a male preponderance in 3K mice in that females show less lowering of the αS T:M ratio and increased autophagic turnover of αS+ lipid-rich brain aggregates.…”

“…10,22 The striking PD-like motor syndrome of 3K mice includes resting tremor, bradykinesia, rigidity, and gait deficits that respond in part to L-dopa treatment, while relatively subtle changes in forced gait patterns are observed in male WT αS-overexpressing mice versus their female counterparts. 22 Similar to PD, 23 there is a male preponderance in 3K mice in that females show less lowering of the αS T:M ratio and increased autophagic turnover of αS+ lipid-rich brain aggregates. 22 These multiple features make the 3K model highly suitable for the necessary preclinical testing of potentially disease-modifying approaches to PD.…”