Abstract
Neuronal loss in Parkinson’s disease and related brain diseases has been firmly linked to the abundant neuronal protein α-synuclein (αS). However, we have gained surprisingly little insight into how exactly αS exerts toxicity in these diseases. Hypotheses of proteotoxicity, disturbed vesicle trafficking, mitochondrial dysfunction and other toxicity mechanisms have been proposed, and it seems possible that a combination of different mechanisms may drive pathology. A toxicity mechanism that has caught increased attention in the recent years is αS-related lipotoxicity. Lipotoxicity typically occurs in a cell when fatty acids exceed the metabolic needs, triggering a flux into harmful pathways of non-oxidative metabolism. Genetic and experimental approaches have revealed a significant overlap between lipid storage disorders, most notably Gaucher’s disease, and synucleinopathies. There is accumulating evidence for lipid aberrations causing synuclein misfolding as well as for αS excess and misfolding causing lipid aberration. Does that mean the key problem in synucleinopathies is lipotoxicity, the accumulation of harmful lipid species or alteration in lipid equilibrium? Here, we review the existing literature in an attempt to get closer to an answer.
Highlights
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Citation: Tripathi, A.; Fanning, S.; Dettmer, U
1. α-Synuclein and Synucleinopathies α-Synuclein is an abundant protein of 140 residues present in all human neuron types. αS biology has attracted great interest given its association with a group of devastating neurodegenerative disorders known as synucleinopathies, the most prevalent of which is Parkinson’s disease (PD), followed by dementia with Lewy bodies (DLB) and multiple system atrophy (MSA)
A recent characterization of LBs by correlative light and electron microscopy (CLEM) came to surprising conclusions: fibrillar αS aggregates were found in about 20% of LBs and LNs examined, while abundant crowded organelles such as mitochondria, vesicle clusters and lipid membranes were detected in the core, which were coated with high concentration of non-fibrillar αS [15]
Summary
A recent characterization of LBs by correlative light and electron microscopy (CLEM) came to surprising conclusions: fibrillar αS aggregates were found in about 20% of LBs and LNs examined, while abundant crowded organelles such as mitochondria, vesicle clusters and lipid membranes were detected in the core, which were coated with high concentration of non-fibrillar αS [15]. When induced pluripotent stem cell (iPSC)-derived human neurons were lentivirally transduced to express αS, neutral and phospholipids were found to be altered, with the most notable change being increased TGs [36]. The high extent of LDitincrease, e.g., in yeast [35], be consistent reduced(e.g., by αS binding In this regard should be mentioned thatwould a strategic amplification with feedback mechanism that increase lipid de novo generation when turnover re- LDs of αS E46K (‘3K’ = E35K+E46K+E61K) was found to be strongly associatediswith duced by αS binding. It mutants that exhibit strongly enhanced LD binding [62,65,66] may be useful tools to elushould be noted, that increased LDs in cells are not necessarily per se detrimental cidate signaling events that elevate (harmful) lipid species in experimental settings ΑS excess which comprises the accumulation of free FAs, DGs, TGs and oleic acid. αS excess at membranes (small red ovals, bottom right) causes vesicle clustering and/or trafficking defects. αS, α-synuclein; FA, fatty acid; DG, diacylglycerol; TG, triacylglycerol
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