Moors TE, Li S, McCaffery TD, Ho GP, Bechade PA, Pham LN, Ericsson M, Nuber S. Increased palmitoylation improves estrogen receptor alpha-dependent hippocampal synaptic deficits in a mouse model of synucleinopathy. Sci Adv. 2023 Nov 15;9(46):eadj1454. Epub 2023 Nov 17 PubMed.

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  1. Underlying causes of sex differences in PD susceptibility is something of a black box, and these studies are headed in the right direction. The experiments are technically excellent, and the data are very clear.

    More studies focused on this important problem are needed. One issue is that it is not clear if gender differences in PD models that genetically overexpress WT or mutant α-synuclein are relevant in the context of sporadic Parkinson’s disease, where these gender difference are actually seen. However, there is no easy way to address these questions.

    View all comments by Subhojit Roy

  2. This publication builds on Silke Nuber’s work on sex differences in PD in vivo models (Rajsombath et al., 2019), and that of Dennis Selkoe and Gary Ho on palmitoylation modifying αS PD phenotypes including neurotoxicity and αS accumulation (Ho et al., 2021; Ho et al., 2023).

    The new paper makes several important contributions to the field of PD. It progresses our understanding of differences in PD in females and males in vivo. It is an exciting advance in determining an early αS-induced synaptic impairment, partly contributed by palmitoylated ERα. It furthers mechanistic insight on synaptic changes in males versus females and supports palmitoylation modification as a candidate therapeutic approach.

    The group discerns an abnormal distribution of ERα in 3KL mice associated with reduced palmitoylation. Treatment with the APT1 inhibitor ML348 improved aberrant cognitive and motor phenotypes, correlating with restoring synaptic plasticity. Of particular interest is the correlation of cognitive function in 6-month-old 3KL females with increased αS multimers and αS solubility. This advances understanding of the intimate connection between αS conformation (multimers), αS solubility, and αS localization with PD phenotypes in vivo, highlighting the importance of this aspect of αS biology in PD.

    References:

    Rajsombath MM, Nam AY, Ericsson M, Nuber S. Female Sex and Brain-Selective Estrogen Benefit α-Synuclein Tetramerization and the PD-like Motor Syndrome in 3K Transgenic Mice. J Neurosci. 2019 Sep 18;39(38):7628-7640. Epub 2019 Aug 12 PubMed.

    Ho GP, Ramalingam N, Imberdis T, Wilkie EC, Dettmer U, Selkoe DJ. Upregulation of Cellular Palmitoylation Mitigates α-Synuclein Accumulation and Neurotoxicity. Mov Disord. 2021 Feb;36(2):348-359. Epub 2020 Oct 26 PubMed.

    Ho GP, Wilkie EC, White AJ, Selkoe DJ. Palmitoylation of the Parkinson's disease-associated protein synaptotagmin-11 links its turnover to α-synuclein homeostasis. Sci Signal. 2023 Feb 14;16(772):eadd7220. PubMed.

    View all comments by Saranna Fanning

  3. This is elegant work by my colleagues Silke Nuber, Tim Moors, and team. It combines sexual dimorphism and protein palmitoylation to reinforce the view that synaptic dysfunction is one of the key drivers of early synuclein pathology. While the results are encouraging, and modulating synaptic function is a potential disease-modifying therapy, we have to wait and see the therapeutic value of palmitoylated estrogen receptor-α (ER-α).

    Some of the open questions that the team may already be addressing include:

    1) whether ER-α palmitoylation is reduced in Parkinson’s disease and Lewy body dementia patients,

    2) what does it mean that in early pathology, ER-α palmitoylation appears to be not different between male and female 3K-low mice,

    3) what is the functional relevance of palmitoylated ER-α in restoring synaptic deficits in synucleinopathy.

    As the Nuber team points out, the latter may particularly be challenging because of the lack of feasible options, but it will be important.

    View all comments by Nagendran Ramalingam

  4. This is a thought-provoking study by my colleagues at BWH. Moors et al. build on the lab’s previous insight into how female sex may protect from α-synuclein pathology. Digging deeper into the mechanism(s), this paper identifies estrogen-receptor α as a key player.

    Previous work by other groups has shown that estrogen-receptor α is found at synapses, attached to synaptic vesicles via a palmitoyl anchor.

    It seems to have a positive effect on synaptic transmission, possibly by increasing the mobility of synaptic vesicles.

    In that role, estrogen-receptor α may have two beneficial effects on αS-related pathology: (1) it counteracts the vesicle accumulation/aggregation that seems to be triggered by α-synuclein excess at membranes; (2) it helps get α-synuclein off the vesicle membranes. Unsurprisingly, both roles seem to depend on proper palmitoylation. This offers a regulatory step that, who knows, may become druggable by specific compounds (the ML438 drug used in the study is not specific to estrogen-receptor α palmitoylation).

    However, while estrogen-receptor α seems to be a good influence on α-synuclein, α-synuclein seems to be a bad influence on estrogen-receptor α: excess membrane α-synuclein may interfere with estrogen-receptor α palmitoylation, leading to mislocalization and loss of function.

    As the authors correctly point out, the intriguing findings from the “3K” mouse model of α-synuclein membrane excess will need to be tested in other models, including models of α-synuclein cytosolic accumulation or seeded α-synuclein aggregation. Different outcomes in such models, however, would not necessarily question the role of estrogen-receptor α in membrane-mediated α-synuclein toxicity. It could also help differentiate between different pathways to α-synuclein toxicity, identifying the respective key players. It looks like estrogen-receptor α may very well be such a player, at least in a subset of synucleinopathies.

    View all comments by Ulf Dettmer

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