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Disrupted Fat Breakdown in the Brain of Mice Makes Them Dumb

Summary: Blocking the breakdown of a specific fat molecule in the the brains of mice lead to reduced learning ability and memory retention. Additionally, researchers noted an increase of Alzheimer’s related proteins. Findings may help explain how dementia may develop in humans, researchers say.

Source: University of Bonn.

Study led by the University of Bonn elucidated a previously unknown possible cause of dementia.

A study led by the University of Bonn opens a new perspective with regard to the development of dementia. The scientists blocked the breakdown of a certain fat molecule in the mouse brain. As a result the animals exhibited learning and memory problems. Also the quantity of Alzheimer-specific proteins in their brains increased significantly. The researchers now have a clue as to why the mice become dumb. The results are published in the renowned scientific journal “Autophagy”.

Apart from water, our brain is rich in lipids — in plain language: fats. The lipids act, for instance, as an insulating layer around the nerve fibers and thus prevent short circuits. However, they are also a main component in the delicate membranes that surround the brain cells.

Sphingolipids, a special lipid type are highly enriched in the brain. One of their degradation products, S1P, may play a central role in the development of Alzheimer’s and other forms of dementia. “We raised mice that are no longer able to break down S1P in large parts of their brain,” explains Dr. Gerhild van Echten-Deckert. “The animals then displayed severely reduced learning and memory performance.”

Van Echten-Deckert undertakes research at the LIMES Institute at the University of Bonn (the acronym stands for “Life and Medical Sciences”) as an assistant professor. For a long time, she has been one of the few experts in the world interested in the role of S1P in the brain. The new study could fundamentally change this, as the researchers at the University of Bonn, Jena University Hospital, the German Center for Neurodegenerative Diseases (DZNE) and from San Francisco and Madrid were able to show what far-reaching consequences disrupted S1P breakdown has.

“Self-eating” keeps the brain healthy

Normally, S1P is broken down into simpler products. One such breakdown product generated is important for a vital metabolic pathway – called autophagy. The word autophagy (literally translates to “self-eating”) and the pathway enables cells to digest and recycle their own components. The cells are thus cleared from defective proteins and cell organelles that no longer function properly.

Intracellular waste disposal works in two steps: first, it packs the waste in tiny “garbage bags”. These then merge with other “bags” that contain highly reactive enzymes. The enzymes “shred” the content of the garbage bags and thus dispose it off.

Image shows a neuron.

Nerve cells with disrupted s1p breakdown the yellow-orange marked garbage bags have not closed properly, and are therefore transparent. NeuroscienceNews.com image is credited to AG van Echten-Deckert/Uni Bonn.

The break-down product of S1P is involved in packing the waste into the intracellular garbage bags. “If S1P is not broken down, fewer closed garbage bags are formed; autophagy then no longer works accurately,” explains the first author of the study Daniel Mitroi, who has recently completed his PhD at the LIMES Institute. “Harmful substances thus accumulated in the brains of our mice. These included the protein APP, which plays a key role in the development of Alzheimer’s.”

As autophagy is crucial for normal functioning of the brain, improper intracellular waste disposal results in severe illnesses. Therefore last year the Nobel Prize in Medicine was awarded to the Japanese scientist Yoshinori Ohsumi for his notable work on this vital mechanism. The results of the current study shed light on a previously overlooked mechanism for dementia development. “In the long term, our work may contribute towards developing successful treatment strategies for brain disorders,” hopes Dr. van Echten-Deckert.

About this neuroscience research article

Source: Dr. Gerhild van Echten-Deckert – University of Bonn
Image Source: NeuroscienceNews.com image is credited to AG van Echten-Deckert/Uni Bonn.
Original Research: Full open access research for “SGPL1 (sphingosine phosphate lyase 1) modulates neuronal autophagy via phosphatidylethanolamine production” by T. Daniel N. Mitroi, Indulekha Karunakaran, Markus Gräler, Julie D. Saba, Dan Ehninger, María Dolores Ledesma & Gerhild van Echten-Deckert in Autophagy. Published online February 28 2017 doi:10.1080/15548627.2017.1291471

Cite This NeuroscienceNews.com Article
University of Bonn “Disrupted Fat Breakdown in the Brain of Mice Makes Them Dumb.” NeuroscienceNews. NeuroscienceNews, 19 May 2017.
<http://neurosciencenews.com/dementia-fat-s1p-6721/>.
University of Bonn (2017, May 19). Disrupted Fat Breakdown in the Brain of Mice Makes Them Dumb. NeuroscienceNew. Retrieved May 19, 2017 from http://neurosciencenews.com/dementia-fat-s1p-6721/
University of Bonn “Disrupted Fat Breakdown in the Brain of Mice Makes Them Dumb.” http://neurosciencenews.com/dementia-fat-s1p-6721/ (accessed May 19, 2017).

Abstract

SGPL1 (sphingosine phosphate lyase 1) modulates neuronal autophagy via phosphatidylethanolamine production

Macroautophagy/autophagy defects have been identified as critical factors underlying the pathogenesis of neurodegenerative diseases. The roles of the bioactive signaling lipid sphingosine-1-phosphate (S1P) and its catabolic enzyme SGPL1/SPL (sphingosine phosphate lyase 1) in autophagy are increasingly recognized. Here we provide in vitro and in vivo evidence for a previously unidentified route through which SGPL1 modulates autophagy in neurons. SGPL1 cleaves S1P into ethanolamine phosphate, which is directed toward the synthesis of phosphatidylethanolamine (PE) that anchors LC3-I to phagophore membranes in the form of LC3-II. In the brains of SGPL1fl/fl/Nes mice with developmental neural specific SGPL1 ablation, we observed significantly reduced PE levels. Accordingly, alterations in basal and stimulated autophagy involving decreased conversion of LC3-I to LC3-II and increased BECN1/Beclin-1 and SQSTM1/p62 levels were apparent. Alterations were also noticed in downstream events of the autophagic-lysosomal pathway such as increased levels of lysosomal markers and aggregate-prone proteins such as APP (amyloid β [A4] precursor protein) and SNCA/α-synuclein. In vivo profound deficits in cognitive skills were observed. Genetic and pharmacological inhibition of SGPL1 in cultured neurons promoted these alterations, whereas addition of PE was sufficient to restore LC3-I to LC3-II conversion, and control levels of SQSTM1, APP and SNCA. Electron and immunofluorescence microscopy showed accumulation of unclosed phagophore-like structures, reduction of autolysosomes and altered distribution of LC3 in SGPL1fl/fl/Nes brains. Experiments using EGFP-mRFP-LC3 provided further support for blockage of the autophagic flux at initiation stages upon SGPL1 deficiency due to PE paucity. These results emphasize a formerly overlooked direct role of SGPL1 in neuronal autophagy and assume significance in the context that autophagy modulators hold an enormous therapeutic potential in the treatment of neurodegenerative diseases.

“SGPL1 (sphingosine phosphate lyase 1) modulates neuronal autophagy via phosphatidylethanolamine production” by T. Daniel N. Mitroi, Indulekha Karunakaran, Markus Gräler, Julie D. Saba, Dan Ehninger, María Dolores Ledesma & Gerhild van Echten-Deckert in Autophagy. Published online February 28 2017 doi:10.1080/15548627.2017.1291471

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