A Stearoyl-CoA Desaturase Inhibitor Prevents Multiple Parkinson’s Disease-Phenotypes in α-Synuclein Mice
This week we profile a recent publication in Annals of Neurology from the laboratories of Dr. Silke
Nuber (pictured, left) and Dennis Selkoe (right) at Brigham and Women’s Hospital.
What is the significance of the findings in this publication?
The α-synuclein protein accumulates in Parkinson’s disease (PD) and other synucleinopathies. Growing evidence suggests that lipid-rich vesicle clusters containing α-synuclein form the basis of the neuropathological Lewy bodies. Recent research indicates that an excess of α-synuclein monomers at membranes deriving from decreased ability to form physiological tetramers may be a key to its neurotoxicity. In new work published in Annals of Neurology, researchers led by Silke Nuber and Dennis Selkoe at the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital describe benefits when treating with inhibitors of the enzyme stearoyl-CoA desaturase (SCD) in two α-synuclein mouse models. One model overexpresses human wild-type (WT) α-synuclein (as occurs in most PD cases); the other expresses an amplified fPD E46K-like mutant (called ‘3K’) that decreases the normal α-synuclein tetramer-to monomer (T:M) ratio and develops lipid-rich clumps and profound PD-like motor deficits (see Nuber et al, Neuron, 2018; Rajsombath et al., J Neurosci, 2019). Both transgenic mice developed phospho-serine129+ α-synuclein aggregates and motor deficits, but more prominently in the 3K than the WT mice. Decreasing lipid mono-unsaturation (e.g., C16:1) by feeding the SCD-inhibitor ‘5b’ led to more α-synuclein tetramers in brain neurons, thus preventing (in WT mice) or ameliorating (in 3K mice) the α-synuclein membrane-association, lipid aggregates and resultant gait abnormalities. After 4 months of 5b treatment, mice had ~20% more C16:0, associated with decreased lipid-rich aggregate formation, improved dopamine levels and better gait balance.
Of relevance, a study led by David Klenerman at the University of Cambridge in 2016 found that the polyunsaturated fatty acid arachidonic acid (20:4) facilitated formation and stabilization of a-helical tetramers/multimers of α-synuclein, preventing cytotoxicity (Iljina et al., Science Reports, 2016). Separately, increased neuronal glycosylsphingolipids by GBA1 loss-of function (Gaucher’s) mutations (a major PD-risk factor) decreased the α-synuclein T:M ratio, while miglustat, which decreased glucosylceramide levels, increased the T:M ratio in human GBA1-PD neurons (Kim et al., PNAS, 2018). More recently, two groups showed that decreasing fatty acid unsaturation by SCD inhibition prevented α-synuclein toxicity in Parkinson’s neuronal models and increased α-synuclein multimerization in 3K-expressing neurons (Fanning et al, Molecular Cell, 2018; Vincent et al., Cell Reports, 2018). These observations suggest that α-synuclein can shuttle in and out of multimeric assemblies, promoting a dynamic T:M equilibrium. Collectively, these various results suggest that interfering with certain unsaturated fatty acids and their associated brain lipids could treat neurodegeneration and early motor impairments in PD.
That stabilizing the α-synuclein T:M ratio is beneficial fits with previous findings of the Nuber lab that female sex or treating males with estradiol improved α-synuclein tetramer levels and delayed motor phenotypes in the PD-like mice. Given growing findings that Lewy bodies contain lipid-rich material and α-synuclein aggregates, researchers have advanced the idea that it is not only the α-synuclein fibrillization process that is toxic (Shamoradian et al., Nat Neurosci 2019). One explanation from findings by Chandra and Westphal at Yale (JBC 2013) is that only a physiological level of α-synuclein monomers can correctly bend membranes, promoting normal endocytosis. Another idea is that normal levels of α-synuclein tetramers/multimers protect synapses by vesicle binding and chaperoning, as studies by Tom Südhof (Burre et al., PNAS, 2014) and Subhojit Roy (Wang et al., PNAS, 2014) have suggested.
The Nuber and Selkoe teams propose that the physiological α-synuclein T:M equilibrium protects synapses by allowing normal vesicle tethering and exocytosis. These various mechanisms may co-occur and are not mutually exclusive.
What are the next steps for this research?
Nuber, Selkoe and colleagues will further examine protective mechanisms that improve α-synuclein T:M homeostasis in PD-like models and focus on correcting the underlying lipid changes, with attendant therapeutic implications for humans.
This work was funded by:
Funded by an NIH R01 (NS109510), a MJFF research grant (16296) and a gift of the WBI to SN; and a NIH R01 (NS083845) to DS.