Enzyme Linking Fatty Acids to Alpha-synuclein Could Be Parkinson’s Therapeutic Target, Study Suggests

alpha-synuclein, fatty acids

Inhibiting an enzyme that regulates the production of fatty acids may protect against brain toxicity induced by alpha-synuclein in Parkinson’s disease and may become a therapeutic target for these patients, a study reports.

The study, “Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment,” was published in the journal Molecular Cell.

The brain is rich in lipids, or fats, which are key for neural development and nerve cell communication. Brain cells tightly regulate lipid production and uptake, as well as the distribution of its precursors, such as fatty acids. Imbalance of the brain’s lipids has been implicated in several neurodegenerative diseases, including Parkinson’s.

Alpha-synuclein, the main component of protein clumps known as Lewy bodies, interacts with fatty acids and favors their storage as triglycerides — the most common type of fat in the body — in lipid droplets in cells.

These droplets prevent the toxic effects of lipid accumulation, but may also contribute to the deposition of alpha-synuclein. Proteins related to lipid metabolism have been identified as risk factors for Parkinson’s. However, little is known about the impact of lipid metabolism on alpha-synuclein assembly and cellular alterations.

Researchers first measured lipids and fatty acid alterations in yeast that had been engineered to produce alpha-synuclein. This showed an increase in components of the neutral lipids pathway — storage lipids lacking positively and/or negatively charged groups — including a monounsaturated fatty acid called oleic acid. The team thereby hypothesized that high oleic acid levels promote the binding of alpha-synuclein to the cell membrane, increasing toxicity.

These findings were then replicated in patient cell lines, in a mouse model of familial Parkinson’s, and in a model of dopamine-producing neuron degeneration (a hallmark of Parkinson’s) in the nematode worm Caenorhabditis elegans.

“It was fascinating to see how excess [alpha-synuclein] had such consistent effects on the neutral lipid pathway across model organisms,” Ulf Dettmer, PhD, co-senior author of the study from the Brigham and Women’s Hospital and Harvard Medical School, said in a press release. “All our models clearly pointed at oleic acid as a mediator of [alpha]-synuclein toxicity.”

Researchers investigated possible ways to target fatty acids or the processes leading to their production that could protect against Parkinson’s. They found that triglycerides protect from alpha-synuclein-induced toxicity by preventing the accumulation of oleic acid and diglyceride, a type of fat composed of two fatty acid chains.

Importantly, they found that inhibiting an enzyme known as stearoyl-CoA-desaturase (SCD), which is key in the production of oleic acid, protected against cell toxicity, formation of alpha-synuclein aggregates, and a decrease in the amount of protective alpha-synuclein tetramers (natural structure formed by four subunits) relative to its aggregation-prone monomers, or single-protein chains.

“Our findings thus indicate that partial inhibition of SCD would be a rational therapeutic approach to [alpha-synuclein] neurotoxicity,” the researchers wrote.

“We’ve identified a pathway and a therapeutic target that no one has pursued before,” said Saranna Fanning, PhD, the study’s lead author.

Co-senior author Dennis Selkoe, MD, said the findings present “a unique opportunity for small-molecule therapies to inhibit the enzyme in models of [Parkinson’s] and, ultimately, in human diseases.”

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LRRK2 Worthy Target of Research into Parkinson’s Therapies, Study Suggests

LRRK2 mutations

A perspective article summarizes what researchers have learned so far on the role of LRRK2 mutations in the development of Parkinson’s disease, and recommends the enzyme as a target for therapy development.

The report, “LRRK2 kinase in Parkinson’s disease,” was published in the journal Science.

Although the vast majority of Parkinson’s cases are idiopathic, or of unknown cause, LRRK2 mutations — the leading genetic cause of this disease — account for about 1 to 2 percent of all cases. Mutations in this gene increase the risk of developing Parkinson’s due to an LRRK2-increased risk of neuronal death.

About 20 LRRK2 mutations have been linked with the disease, and its incidence can be higher in some populations such as the Ashkenazi Jews and North African Berbers.

The LRRK2 gene codes for the enzyme leucine-rich repeat kinase 2 (LRKK2), a protein that modifies other proteins’ activities, including signaling, replication, and gene expression.

All LRRK2 disease-causing mutations lead to higher LRKK2 enzyme activity; as such, researchers believe that inhibiting or blocking its activity can be used as a potential therapeutic target.

In fact, two LRRK2 inhibitors are currently being evaluated to treat Parkinson’s in two Phase 1 trials. The experimental therapies, called DNL-201 and DNL-151, are being developed by Denali Therapeutics. So far, DNL201 has stopped an average 90 percent of LRRK2 kinase activity at its highest concentration. When the drug’s levels dropped to the lowest concentration, it still inhibited on average 50 percent of such activity.

Studying the effects of LRRK2 mutations also provides an opportunity to better understand how Parkinson’s disease unravels, the study notes.

Recent advances support that LRRK2 modifies a group of proteins, called Rab GTPases, that regulate diverse cellular processes.

These proteins play important roles in immune responses and vesicular trafficking — the transport and recycling of materials inside the cell through a system of vesicles.

Disruption of RAB-related transport may also promote accumulation of alpha-synuclein aggregates inside neurons, a hallmark of Parkinson’s disease.

LRRK2 is also thought to be linked to inflammation, a process that plays an important part in disease development. LRRK2  is highly expressed  in several immune system cells, including macrophages,  monocytes, and neutrophils. 

“Research indicates that, in early  life, increased LRRK2 activity may protect against opportunistic  pathogenic infection but then later increases the risk of developing Parkinson’s disease,” the researchers write.

LRRK2-associated Parkinson’s closely resembles idiopathic disease in terms of its late age of onset and  symptoms. But several factors seem to influence the ability of LRRK2 mutations to cause disease, including age and the type of mutation.

People carrying some types of mutations, such as G2019S, may never develop Parkinson’s, while nearly all of those bearing the R1441G mutation eventually will.

One case report in twins carrying the same LRRK2 mutation found only one developed Parkinson’s. This highlights the importance of environmental factors and lifestyle (smoking, exercise, diet), as well as the gut microbiome and infection in the development of LRRK2-dependent Parkinson’s.

“However, for now, the most exciting question will be whether LRRK2 inhibitors have disease-modifying effects in PD patients with LRRK2 mutations,” the researchers wrote.

The authors stress that preclinical studies in animal models indicate potential toxicity of LRRK2 inhibitors to the lungs and kidneys, and recommend special attention be taken to monitor toxicity in these organs in human clinical trials. 

Given the role of LRRK2 in fighting infections, it will also be important to establish whether blocking LRRK2 increases the risk of opportunistic infections. But, overall, the scientists believe that “LRRK2 is a possible therapeutic target for Parkinson’s disease.”

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Source: Parkinson's News Today