Fanning S, Haque A, Imberdis T, Baru V, Barrasa MI, Nuber S, Termine D, Ramalingam N, Ho GP, Noble T, Sandoe J, Lou Y, Landgraf D, Freyzon Y, Newby G, Soldner F, Terry-Kantor E, Kim TE, Hofbauer HF, Becuwe M, Jaenisch R, Pincus D, Clish CB, Walther TC, Farese RV Jr, Srinivasan S, Welte MA, Kohlwein SD, Dettmer U, Lindquist S, Selkoe D. Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment. Mol Cell. 2019 Mar 7;73(5):1001-1014.e8. Epub 2018 Dec 4 PubMed.
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University of Alabama at Birmingham
This is an interesting but complex study by Fanning and colleagues.
My takeaway is that there are two inter-related themes here: increased α-synuclein leads to changes in lipid metabolism; and alterations in lipids can modulate the toxicity of α-synuclein. While both are of interest, I think the data on the effect of oleic acid on α-synuclein toxicity in Fig. 4 is the most intriguing. They show nicely that the abundance of oleic acid can modulate the aggregation and toxicity of α-synuclein. I think of this as part of the broader class of targets that seems to modulate aggregation and toxicity of α-synuclein, which also includes factors that modulate trafficking, lysosomal function, and chaperone proteins. Oleic acid, however, may be more amenable to therapeutic intervention than some of these other pathways.
An obvious next step is to take this approach into an intact mammalian model system. I will be interested to see how this turns out.
View all comments by David StandaertDenali Therapeutics
Model organisms are increasingly exploited to identify disease mechanisms and suggest novel therapies. Fanning et al. capture the essence of the work of late Susan Lindquist and her legacy, shared with Dennis Selkoe and colleagues, by providing an elegant illustration of how a molecular genetic study in yeast focusing on α-synuclein (αS) uncovers a potential molecular mechanism underlying neurotoxicity associated with Parkinson’s disease (PD) as well as a candidate therapeutic.
It has been known for a long time that the biology of aS is intimately linked to that of membrane lipids, primarily reflecting the ability of this protein to physically interact with anionic phospholipids present in various organelles, including synaptic vesicles. This interaction is critical to the physiological function of aS at synapses and is severely perturbed in several PD-linked mutants, affecting its ability to oligomerize, aggregate, and undergo degradation in cells through various mechanisms. This new study focuses on a vastly distinct aspect of lipid biology related to aS toxicity and rather focuses on so-called glycerolipids and fatty acids, such as oleic acid. In fact, earlier studies in the Lindquist lab laid the foundation for this study by showing that overexpressing aS in budding yeast is toxic and interferes with the early biosynthetic pathway, a phenomenon reflecting the ability of aS to modulate vesicular traffic along intracellular compartments and rescued by overexpression of Rab1. Additionally, separate studies from the same lab showed that aS overexpression in yeast leads to the formation of lipid droplets (LDs), which are organelles that are generated from the early biosynthetic pathway (i.e., the endoplasmic reticulum) and store neutral lipids such as triacylglycerol (TG), diacylglycerol (DG), and sterol esters. However, the specific molecular mechanisms leading to aS toxicity in yeast were unknown, and whether those mechanisms applied to neurons was unclear as well.
Collaborating with world experts in lipid biology, such as Tobias Walther, Robert Farese, Sepp Kohlwein and Supriya Srinivasan, Selkoe, Lindquist, and colleagues were able to identify a rather specific mechanism accounting for the toxicity of aS and it relates to lipid toxicity. It is well known in the field of lipid biology that storing specific lipids, such as fatty acids and sterols in LDs, is a process that prevents lipid toxicity, as excess fatty acids or cholesterol is deleterious to cells. In the case of fatty acids, their storage in the form of glycerolipids, such as DG and TG, also represents a major source of energy that can be mobilized by cytosolic lipases or macrolipophagy (i.e., a form of autophagy that clears lipid droplets in lysosomes). Here, by interfering with various factors controlling glycerolipid and fatty-acid metabolism as well as LD dynamics through a number of genetic manipulations, and combined with comprehensive lipidomic analyses, the authors showed that formation of LDs induced by aS overexpression is protective. In essence, preventing TG synthesis in LDs or LD formation drastically enhances aS-related cytotoxicity in yeast, whereas enhancing lipid storage capacity is protective. The authors were able to narrow down the toxicity mechanism to at least two precursor lipids for TG synthesis: DG and the fatty acid, oleic acid (OA). Specifically, channeling excess DG into another pathway for phospholipid synthesis and decreasing production of OA are both protective. The latter mechanism was further exploited and lays the foundation for a potential therapeutic approach.
Since OA, a fatty acid with 18 carbons and one unsaturation, was identified as a mediator of αS toxicity, it was logical to assume that the rate-limiting enzyme for its synthesis, the Δ9 FA desaturase encoded by yeast gene Ole1 and homologous to the mammalian stearoyl-CoA desaturase (SCD), would underlie this toxicity. Indeed, ablating Ole1 in yeast abolished αS toxicity and corrected trafficking defects induced by αS overexpression. The next critical question was to determine whether these striking, yeast-based mechanisms could be extrapolated to mammalian neurons with the added challenge that LD biology has not been much studied in neurons, in part based on scant evidence these organelles appear in CNS neurons, at least in vivo. While this potentially questions the pathophysiological significance of observations made in cell culture, an alternate view may be that the reduced ability of neurons to generate abundant LDs may precisely sensitize them to lipid toxicity. With these considerations in mind, the authors provided evidence that their yeast findings generally translate into cultured rat cortical neurons, albeit with a somewhat less striking outcome and similar concerns about αS overexpression. Nevertheless, various molecular genetic manipulations in rat cortical neurons did confirm that αS toxicity can be attenuated by reducing DG and OA levels, the latter being achieved by silencing or pharmacologically inhibiting SCD. Besides validating this neurotoxic pathway in dopaminergic neurons in the worm, the authors further addressed its pathophysiological significance by studying it in human iPSC-derived neurons overexpressing αS, expressing higher αS levels via gene triplication (which causes PD), and expressing endogenous levels of the disease mutant E46K. While the relevant lipid changes were not as striking, they did show alteration in glycerolipid and unsaturated fatty acid metabolism consistent with those reported in yeast, and somewhat consistent with those found in the brains of mice expressing the familial PD-linked αS mutant E46K.
How does this translate into αS-mediated toxicity and aggregation? The authors provided a potential explanation, focusing on several aspects of αS-related phenotypes observed in a neuroblastoma cell line overexpressing αS, such as formation of inclusions. Pharmacological inhibition and reducing levels of SCD1 were both able to decrease αS cytotoxicity, inclusions, hyperphosphorylation, and the tetramer-monomer ratio (previously shown to reduce aggregate formation). Interestingly, Vincent and colleagues reported independent findings supporting the notion that SCD inhibition may be beneficial in human iPSC-derived neurons expressing various forms of αS, however, starting from a phenotypic screen in yeast. The enrichment of both DG and OA-containing lipids in lipid bilayers is known to destabilize membranes and alter their curvature, likely affecting the ability of αS to interact with them and oligomerize. Additional work will be required to precisely delineate the mechanisms through which lipids affect the behavior of αS, its propensity to oligomerize, aggregate, and exert its neurotoxicity.
Is SCD a viable drug target? While results from both papers are promising, the road to the clinic is long and intricate, as it is for all candidate targets. Some of the fundamental aspects that will have to be addressed along the way include demonstrating proof of concept that manipulating the SCD pathway shows efficacy in preclinical models of familial PD (expressing mutant forms of αS), with the caveat that at least two related isoforms of SCD are expressed in the brain, SCD1 and SCD5. Are these two isoforms expressed in dopaminergic neuron populations that are vulnerable in PD and other synucleinopathies? Is inhibition of one or both required to achieve efficacy? Use of mouse genetics combined with the development of brain-penetrant, potentially isoform-specific compounds should facilitate this endeavor. Another concern in the evaluation of drug targets is the potential safety liabilities. SCD inhibitors have been considered for peripheral indications, including diabetes and liver steatosis, and appear to be relatively well tolerated, despite early concerns raised in preclinical studies. There may be brain-specific safety concerns related to manipulating this pathway in CNS neurons and potentially other cell types in the CNS, including oligodendrocytes, astrocytes, and microglia. Of note, accumulation of OA-containing neutral lipids in ependymal cells of an Alzheimer’s disease (AD) mouse models has been shown to interfere with the proliferation of neural stem cells in the forebrain, and SCD inhibition rescued these proliferative defects (Hamilton et al., 2015). Before that, another study found that SCD is upregulated in AD patients’ brain (Astarita et al., 2011). Overall, there is a growing interest for the SCD pathway in the area of neurodegenerative disorders, and future work should establish whether it can be manipulated in a beneficial way. In the absence of direct genetic evidence linking the SCD genes to PD, AD, or other neurodegenerative disorders, it will be also essential to establish that this pathway is activated in disease. Finally, given the recently-identified genetic associations of other genes operating in DG or fatty acid metabolism with PD (i.e., DGKQ and ELOVL7) (Chang et al., 2017), mechanistic studies exploring these connections will be informative.
References:
Hamilton LK, Dufresne M, Joppé SE, Petryszyn S, Aumont A, Calon F, Barnabé-Heider F, Furtos A, Parent M, Chaurand P, Fernandes KJ. Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer's Disease. Cell Stem Cell. 2015 Oct 1;17(4):397-411. Epub 2015 Aug 27 PubMed.
Astarita G, Jung KM, Vasilevko V, Dipatrizio NV, Martin SK, Cribbs DH, Head E, Cotman CW, Piomelli D. Elevated stearoyl-CoA desaturase in brains of patients with Alzheimer's disease. PLoS One. 2011;6(10):e24777. PubMed.
Chang D, Nalls MA, Hallgrímsdóttir IB, Hunkapiller J, van der Brug M, Cai F, International Parkinson's Disease Genomics Consortium, 23andMe Research Team, Kerchner GA, Ayalon G, Bingol B, Sheng M, Hinds D, Behrens TW, Singleton AB, Bhangale TR, Graham RR. A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci. Nat Genet. 2017 Oct;49(10):1511-1516. Epub 2017 Sep 11 PubMed.
View all comments by Gilbert Di PaoloThe Cure Parkinson's Trust
This research truly validates the late Prof. Susan Lindquist's novel idea of using yeast to study neurodegeneration—an idea which in the early 2000s was considered "crazy" even by people in her own lab (see New York Times article). And the fact that this research is now resulting in compounds being developed for clinical testing only further cements an amazing legacy for Prof. Lindquist.
All of that said, the clinical translation of stearoyl-CoA-desaturase (SCD) inhibition may face significant challenges. We know that SCD inhibition can have both beneficial and detrimental effects depending on context. For example, while inhibition of SCD may reduce α-synuclein toxicity in the brain, in models of colitis it exacerbates proinflammatory responses (Chen et al., 2008). In addition, in various preclinical models of diabetes, SCD inhibition has been reported to have completely different effects depending on the model used (Flowers et al., 2007). Thus, in a scenario reminiscent of the early LRRK2 inhibitors, there could be complications in non-CNS tissues that will need to be addressed.
While this new finding is tremendously exciting and highlights novel areas of research for the Parkinson's community, some caution may be required moving forward toward the clinic.
References:
Chen C, Shah YM, Morimura K, Krausz KW, Miyazaki M, Richardson TA, Morgan ET, Ntambi JM, Idle JR, Gonzalez FJ. Metabolomics reveals that hepatic stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis. Cell Metab. 2008 Feb;7(2):135-47. PubMed.
Flowers JB, Rabaglia ME, Schueler KL, Flowers MT, Lan H, Keller MP, Ntambi JM, Attie AD. Loss of stearoyl-CoA desaturase-1 improves insulin sensitivity in lean mice but worsens diabetes in leptin-deficient obese mice. Diabetes. 2007 May;56(5):1228-39. Epub 2007 Mar 16 PubMed.
View all comments by Simon StottUniversity of California, San Diego
These are exciting findings, with implications for α-synuclein therapeutics and Parkinson's disease. Researchers have known that α-synuclein interacts with lipids for some time, but few therapeutic strategies have exploited this property.
The two papers use different approaches but arrive at the same target—the enzyme stearoyl-CoA desaturase (SCD)—which gives confidence that this is a bona fide target. Overall, the work from both groups shows that reducing levels of SCD decreases α-synuclein-induced toxicity, and thus could be a potential therapeutic avenue in Parkinson’s disease.
While the data in both studies is convincing, the effects need to be validated in established in vivo animal models of Parkinson’s (so far, it seems the results are validated in cell lines, iPSC-neurons, and a C. elegans model). Given that SCD is likely an important enzyme playing myriad roles in maintaining physiology, detailed pharmacologic and toxicity studies are warranted. Advantages of this approach over other means to lower α-synuclein directly are also unclear at this time.
View all comments by Subhojit RoyMake a Comment
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