Fatty Acid Length Predicts Parkinson’s Disease Risk
FeaturedNeurologyNeuroscience
·December 8, 2021
Summary: Chains of fatty acids in the lysosome that are one-half nanometer longer than normal-length chains were associated with a degenerative form of Gaucher disease, a genetic condition related to Parkinson’s disease.
Source: Northwestern University
Whether or not someone develops Parkinson’s disease may be a game of nanometers.
A recent study has demonstrated that chains of fatty acids in the lysosome just one-half nanometer longer than normal-length chains—less than half the diameter of a DNA molecule—were associated with a degenerative form of Gaucher disease, an inherited condition related to Parkinson’s disease.
According to the study publishing in Proceedings of the National Academy of the Sciences (PNAS), the length of these fatty acid or lipid chains could explain why some patients with harmful mutations in the gene GBA1 never develop Parkinson’s disease.
“The people who develop Parkinson’s disease probably accumulate these long chains that are extra sticky and interact with alpha-synuclein,” said Joseph Mazzulli, Ph.D., associate professor in the Ken and Ruth Davee Department of Neurology in the Division of Movement Disorders and senior author of the study. “We hypothesize that the ones who don’t develop Parkinson’s don’t accumulate these long chains, and so are protected.”
Mutations in GBA1 are the most common known genetic risk factor for Parkinson’s disease. A single mutation in the gene leads to an approximately 10 percent chance of developing Parkinson’s, but two mutations—one inherited from each parent—results in the lysosomal storage disorder Gaucher disease, characterized by a failure of the lysosome to dispose of glycosylated fatty acids and subsequent accumulation of those fatty acid chains.
Some but not all patients with Gaucher disease develop a form of the disorder similar to Parkinson’s disease. This mirrors the uncertainty with which GBA1 mutations cause Parkinson’s disease, so Mazzulli and his collaborators examined cellular models of Gaucher disease to elucidate the source of this unexplained risk.
Examining the lysosomes of these cells, the scientists discovered a particular family of lipids that are abnormally long—a difference of one-tenth to one-half nanometer—and which are especially neurotoxic. These lipids stimulate the formation of alpha-synuclein aggregates, clumps of misfolded proteins that are associated with Parkinson’s disease symptoms, Mazzulli said.
This shows long chain lipids
Long-chain lipids (green) accumulate in the lysosomes (red) of disease cultures (right) but not in healthy cells (left). Credit: Northwestern University
Treating the cells with a drug that decreases the levels of long chain length lipids reduced alpha-synuclein aggregates and reversed the neurotoxic phenotype, confirming the long chain length was an operative factor.
Further, the scientists discovered that cathepsin-B, a protein that cuts synuclein in the lysosome, needs to be inactive in addition to the presence of long fatty acid chains in order to produce the neurotoxic phenotype. Inhibiting cathepsin-B in patient-derived neuron cultures blocked the protective effects of the lipid-reducing drug. This new discovery may explain the failure of a recent clinical trial for lipid-shortening drugs in patients with Parkinson’s disease, Mazzulli said.
“We think that patients need to have an active cathepsin-B in order for these drugs to work,” Mazzulli said. “This discovery may help to guide future clinical trials by screening for patients with functional cathepsin-B. Alternatively, combination therapies that activate cathepsin-B while reducing lipids may provide therapeutic benefit.”
Next, Mazzulli said he plans to examine these lipid chain lengths in models of Parkinson’s disease, and believes that the combination of long chain lengths and inactive cathepsin-B could sharpen prediction of Parkinson’s disease risk in patients with GBA1 mutations.
“If we look for lipid chain length and cathepsin-B, these are two factors that can address why some patients get Parkinson’s disease and some do not,” Mazzulli said.
About this Parkinson’s disease research news
Author: Will Doss
Source: Northwestern University
Contact: Will Doss – Northwestern University
Image: The image is credited to Northwestern University
Original Research: Closed access.
“Cell models of lipid-rich α-synuclein aggregation validate known modifiers of α-synuclein biology and identify stearoyl-CoA desaturase” by Thibaut Imberdis et al. PNAS
Abstract
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Cell models of lipid-rich α-synuclein aggregation validate known modifiers of α-synuclein biology and identify stearoyl-CoA desaturase
Microscopy of Lewy bodies in Parkinson’s disease (PD) suggests they are not solely filamentous deposits of α-synuclein (αS) but also contain vesicles and other membranous material. We previously reported the existence of native αS tetramers/multimers and described engineered mutations of the αS KTKEGV repeat motifs that abrogate the multimers.
The resultant excess monomers accumulate in lipid membrane-rich inclusions associated with neurotoxicity exceeding that of natural familial PD mutants, such as E46K. Here, we use the αS “3K” (E35K+E46K+E61K) engineered mutation to probe the mechanisms of reported small-molecule modifiers of αS biochemistry and then identify compounds via a medium-throughput automated screen. αS 3K, which forms round, vesicle-rich inclusions in cultured neurons and causes a PD-like, L-DOPA–responsive motor phenotype in transgenic mice, was fused to YFP, and fluorescent inclusions were quantified.
Live-cell microscopy revealed the highly dynamic nature of the αS inclusions: for example, their rapid clearance by certain known modulators of αS toxicity, including tacrolimus (FK506), isradipine, nilotinib, nortriptyline, and trifluoperazine.
Our automated 3K cellular screen identified inhibitors of stearoyl-CoA desaturase (SCD) that robustly prevent the αS inclusions, reduce αS 3K neurotoxicity, and prevent abnormal phosphorylation and insolubility of αS E46K. SCD inhibition restores the E46K αS multimer:monomer ratio in human neurons, and it actually increases this ratio for overexpressed wild-type αS. In accord, conditioning 3K cells in saturated fatty acids rescued, whereas unsaturated fatty acids worsened, the αS phenotypes.
Our cellular screen allows probing the mechanisms of synucleinopathy and refining drug candidates, including SCD inhibitors and other lipid modulators.
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Tags
brain researchGaucher diseaseGBA1Geneticslong chain fatty acidslysosomeneurobiologyNeurologyNeuroscienceNorthwestern UniversityParkinson's disease
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