Chinese Herbal Medicine Can Ease Brain Inflammation and Protect Neurons, Mice Study Reports

DECEMBER 13, 2018 BY JOANA CARVALHO 

A concoction made from several Chinese herbal medicines helped reduce brain inflammation and promoted nerve cell survival in a mouse model of Parkinson’s disease, a study finds.

The study, “Curative Anti-Inflammatory Properties of Chinese Optimized Yinxieling Formula in Models of Parkinson’s Disease,” was published in Evidence-Based Complementary and Alternative Medicine.

Parkinson’s disease is characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — together with brain inflammation caused by the over-activation of glial cells, which are cells that support and protect neuronal cells, and are more reactive and proliferative than neurons.

“In PD [Parkinson’s disease], neuroinflammation (…) mediated primarily by microglial activation can directly cause DAN [dopaminergic neurons] damage,” the researchers stated. Therefore, finding a way to reduce brain inflammation and prevent glial over-activation “could be an effective method for treating PD.”

The Optimized Yinxieling Formula (OYF), a Chinese concoction of eight different plants, has been used orally to treat patients with moderate and severe psoriasis, an autoimmune disease that affects the skin, characterized by itchy or sore thick patches with silvery scales. The effectiveness of OYF comes from its anti-inflammatory properties, scientists say.

A team of Chinese researchers investigated OYF to treat brain inflammation in a mouse model of Parkinson’s disease. The team found that the herbal medicine successfully blocked the production of pro-inflammatory cytokines (molecules that mediate immune responses) and reduced overall inflammation in mouse glial cells that were activated and cultured in a laboratory dish (in vitro).

As expected, animals treated with MPTP (a neurotoxin that induces Parkinson’s symptoms) showed glial over-activation and poor performance on different behavioral tests. However, when these animals were injected with OYF, glial over-activation was blocked and motor impairments greatly reduced.

To pinpoint the molecular mechanisms responsible for the positive effects of OYF, researchers compared the transcriptome of animals treated with OYF to those receiving a saline solution (control group). The transcriptome is the group of all RNA molecules produced from active genes in a cell or tissue.

Transcriptomic analysis identified 16 signaling pathways responsible for immune system regulation that were highly active in mice treated with OYF. In addition, OYF use lowered the activity of 15 other signaling cascades involved in inflammatory response, “suggesting that the physiological effects of OYF involve key roles of immune and inflammation regulations.”

“[O]ur data showed that OYF can inhibit microglial activation and suppress secretion of proinflammatory cytokines, which collectively protects DAN [dopaminergic neurons] from immune-mediate death,” the researchers said.

“This study suggests that OYF can be used as an effective anti-inflammatory treatment in PD mouse model, providing a novel perspective for the treatment and prevention of PD patients, although more studies of clinical trials in PD might be necessary,” they concluded.

https://parkinsonsnewstoday.com/2018/12/13/brain-inflammation-reduced-parkinsons-chinese-herbal-medicine-study/

Key Parkinson’s Brain Area Implicated in Memory Loss, Study Suggests

DECEMBER 13, 2018 BY JOSE MARQUES LOPES, PHD

Neurodegeneration in the substantia nigra, a critical area of the brain involved in Parkinson’s, leads to memory deficits, according to a study that explored the effects of levodopa on a rat model of the disease.

Findings of the study, titled “Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease,” also illustrated the key role dopamine plays in memory. It was published in the journal Behavioral Brain Research.

Similar to motor symptoms, loss of dopamine-producing neurons in the substantia nigra— a brain area implicated in motor function — has been proposed as the cause of neuropsychiatric manifestations in Parkinson’s disease. This has been shown in animal models, in which bilateral lesion of the substantia nigra (which selectively affects this region only) resulted in anxiety- and depression-like behaviors, as well as motivational, memory and social interaction deficits.  A study in rats also reported psychosis-like behavior in animals subjected to bilateral lesion.

Prior research has shown that chronic dopamine replacement therapy (DRT) — which compensates for the lack of dopamine and represents the standard treatment for different Parkinson’s motor symptoms — leads to impaired ability of neurons to fine-tune their responses in animals and is associated with Parkinson’s-related neuropsychiatric disorders in patients.

After lesion of the nigrostriatal pathway — including the substantia nigra and the dorsal striatum — DRT led to compulsive behavior in animals, which was associated with cellular alterations in brain regions involved in cognitive/affective information processing. Progressive degeneration of the brain’s nigrostriatal pathway — one of the four major dopamine pathways in the brain, involved in production of movement — is a characteristic event in Parkinson’s.

While chronic administration of levodopa worsened lesion-induced anxiety and depression in rats, lesioned primates showed psychotic-like behavior only after dopaminergic treatment.

Biotrial Pharmacology researchers have now evaluated the impact of substantia nigraneurodegeneration, repeated exposure to dopaminergic medication, and the combination of both on the development of neuropsychiatric symptoms of Parkinson’s. The team hypothesized that repeated exposure to levodopa could promote brain remodeling and avoid cognitive-like and affective-like deficits.

The team used a rat model based on bilateral substantia nigra injection of a toxin called 6-hydroxydopamine, which induces selective lesions of specific dopaminergic neurons that do not provoke motor deficits.

A subgroup of animals was repeatedly administered with levodopa (20 mg/kg per day) and benserazide (5 mg/kg daily) via under-the-skin injection over 10 consecutive days (chronic exposure), starting 10 days after partial substantia nigra lesion. Benserazide is an inhibitor of an enzyme called DOPA decarboxylase, which converts levodopa into dopamine.

Behavioral tests were started three weeks after the lesions. These included assessments of spontaneous locomotor activity; forelimb voluntary movement with the stepping test; anxiety-like behavior with the elevated plus maze, in which increased time spent on an open arm correlates with greater anxiety; social interaction, as indicated by the amount of time spent in active non-aggressive social behavior with another rat; memory through novel object recognition; and amphetamine-induced hyperlocomotion (AIH), used to assess responses to psychostimulants.

All animals (both with and without chronic levodopa exposure) received single acute injections of levodopa (12.5 mg/kg)/benserazide (15 mg/kg) before the elevated plus maze and novel object recognition tests.

Results revealed that, in contrast to preserved motor function, lesioned rats showed a significant memory deficit as well as anxiety-like behavior. Social interaction and AIH were unchanged. These animals also demonstrated a 48% decrease in the number of dopaminergic cells within the substantia nigra, whose extent did not correlate with the memory and anxiety results.

Researchers found that a single injection of levodopa/benserazide reversed the memory deficit, but not the anxiety-like behavior. According to the scientists, this suggests that dopaminergic pathways “were less directly involved in lesion-induced anxiety-like behavior.”

Chronic administration of levodopa did not change the results seen in lesioned rats (not chronically exposed), which was contrary to the team’s hypothesis. The investigators attributed this finding to having induced a partial lesion. Studies in more severely injured animals and with longer administrations of levodopa would be of interest, they believe.

The results in the memory test indicate “a not previously clearly identified critical role in cognition for the [substantia nigra],” and illustrate “the critical role of [dopamine] in this behavioural outcome,” the researchers wrote.

According to the team, the findings are in accordance “with clinical data suggesting that a panel of non-motor impairment including cognitive deficit and anxiety may be used as prodromal (early) markers of early stages of [Parkinson’s].”

https://parkinsonsnewstoday.com/2018/12/13/key-parkinsons-brain-area-implicated-memory-loss-study/

New genetic clues to early-onset form of dementia

December 13, 2018 by Jim Dryden, Washington University School of Medicine

The photo shows neurons (red) with a mutation in the MAPT gene — a gene that makes the protein tau. People with this mutation develop frontotemporal dementia. Researchers at Washington University School of Medicine in St. Louis found that cells carrying the MAPT mutation developed abnormalities in genes that control communication between the brain cells. Credit: Sidhartha Mahali

Unlike the more common Alzheimer's disease, frontotemporal dementia tends to afflict young people. It accounts for an estimated 20 percent of all cases of early-onset dementia. Patients with the illness typically begin to suffer memory loss by their early 60s, but it can affect some people as young as their 40s, and there are no effective treatments.

In an effort to better understand the condition, an international team of researchers, led by Washington University School of Medicine in St. Louis, has found that a lone mutation in a single gene that causes an inherited form of frontotemporal dementia makes it harder for neurons in the brain to communicate with one another, leading to neurodegeneration.

The new findings zero in on the MAPT gene. That gene makes a protein called tau, which also has been associated with cognitive decline in Alzheimer's disease. Identifying the downstream effects of the mutation could help identify new treatment targets for frontotemporal dementia, Alzheimer's disease and other tau-related illnesses, including Parkinson's disease.

The study is published Dec. 13 in the journal Translational Psychiatry.

"We have demonstrated that we can capture changes in human cells cultured in a dish that also are appearing in the brains of individuals suffering with frontotemporal dementia," said Celeste M. Karch, Ph.D., an assistant professor of psychiatry and one of the study's senior authors. "Importantly, the approach we are using allows us to zero in on genes and pathways that are altered in cells and in patient brains that may be influenced by compounds already approved by the FDA. We want to evaluate whether any of these compounds could prevent memory loss, or even restore memory, in people with frontotemporal dementia by improving the function of these pathways that have been disrupted."

Karch, with co-senior author Carlos Cruchaga, Ph.D., an associate professor of psychiatry, and the other co-senior author, Oscar Harari, Ph.D., an assistant professor of psychiatry, gathered skin samples from patients with frontotemporal dementia who were known to have a specific mutation in the MAPT gene.

The researchers then converted the patients' skin cells into induced pluripotent stem cells, which have the ability to grow and develop into any cell type in the body. The researchers treated these stem cells with compounds that coaxed them to grow and develop into neurons, which also had the MAPT mutation. Then, using gene-editing technology called CRISPR, the researchers eliminated the mutation in some neurons but not others and observed what happened.

"We found differences in genes and pathways related to cellular communication, suggesting the mutation alters neurons' ability to communicate," said Cruchaga. "The initial mutation in MAPT is the key change that starts the disease, and it is a potential target for therapy, but there are other genes downstream from the MAPT gene that also are good targets that may be used to treat the disease."

In neurons with the mutation, the researchers found alterations in 61 genes, including genes that make GABA receptors on brain neurons. GABA receptors are the major inhibitory receptors in the brain, and they are key to several types of communication between brain cells.

The researchers identified similar disruptions in genes that make GABA receptors when they did experiments in animal models and analyzed brain tissue from patients who had died with frontotemporal dementia. They also looked at findings from a genomewide association study of more than 2,000 patients with frontotemporal dementia and more than 4,000 without the disorder. That analysis also pointed to GABA-related genes as potential targets.

"Using our stem cell-derived neurons, we have the opportunity, in human tissue, to target some of those GABA genes in advance of the neurodegeneration we see in the postmortem tissue we study," said Harari. "So, at least in cell cultures, we can learn whether potential therapies prevent the damage caused by inherited forms of frontotemporal dementia."

And by studying rare, inherited forms of brain diseases, the researchers believe they will learn a great deal about how to treat the more common forms of those disorders.

"Genetic forms of frontotemporal dementia and Alzheimer's disease are caused by rare mutations," Cruchaga said. "But they have much in common with the more typical cases of those diseases. If we understand these cases caused by inherited mutations, we also should better understand the common forms of these diseases."

More information: Jiang S, et al. Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP. Translational Psychiatry, published online Dec. 13, 2018.

Journal reference: Translational Psychiatry 

Provided by: Washington University School of Medicine

https://medicalxpress.com/news/2018-12-genetic-clues-early-onset-dementia.html

Acadia debuts first Nuplazid branded ads, aiming to spark talk of Parkinson's psychosis

 by Beth Snyder Bulik | Dec 12, 2018 

Acadia is appealing to the Parkinson's disease community to raise awareness of psychosis in some patients in its first branded ads for Nuplazid. (Van Andel Research Institute)

With an FDA safety review in the rearview mirror, Acadia is back to business on Parkinson's psychosis therapy Nuplazid—and launching its first branded ad campaign to boot. 

The Nuplazid TV ads made their debut Thanksgiving Day, featuring an older man with Parkinson’s disease who doesn't tell anyone he's been seeing things. His wife notes he “started believing things that weren’t true,” but she too stayed silent. The upshot? Speaking up to a doctor finally helped them understand the hallucinations and delusions that come with Parkinson’s disease.

The ads come two months after the FDA wrapped up a safety check initially sparked by a CNN report. The review concluded in September with no changes to the drug's official safety warnings and information. Nuplazid's label adequately describes its potential side effects, the agency said, affirming that its benefits outweigh its risks.

The new TV and print campaign was built around Acadia market research, which found a knowledge gap about Parkinson's disease psychosis, or PDP. The work aims to raise awareness and offer relatable examples of the hallucinations and delusions that can strike Parkinson's patients, and to help foster discussion about them, said Michael Yang, executive VP and chief commercial officer at Acadia, in an email interview. An estimated 50% of Parkinson's patients have PDP.

The campaign is aimed at the entire Parkinson’s community, including caregivers, healthcare providers and patient advocacy groups, “to help close the Parkinson’s disease psychosis awareness gap and educate about Parkinson’s disease related hallucinations and delusions and Nuplazid as a potential treatment option,” he said.

It was reviewed by advocacy organizations—including the American Parkinson Disease Association, Michael J. Fox Foundation and Parkinson’s Foundation—that agreed it accurately captures the real experiences of patients and their families.

The Nuplazid campaign follows an eight-month unbranded awareness effort about hallucinations and delusions connected to Parkinson’s disease. That awareness effort began in November 2017 and ran through July of this year.

While Nuplazid is Acadia’s only approved drug and is only approved for Parkinson’s, the company is testing the drug for four additional indications and has one other central nervous system drug in its pipeline. Acadia recorded total product revenue of $124.9 million for 2017.

https://www.fiercepharma.com/marketing/acadia-debuts-first-branded-ad-campaign-for-nuplazid-looks-to-draw-awareness-to-parkinson

Tangled Up with Dementia in Parkinson’s Disease

DECEMBER 12, 2018 BY "SHERRI WOODBRIDGE"

A reader recently posed the following question: “Why are there never any comments on dementia in regards to Parkinson’s disease? It is very real, and 40 percent of Parkinson’s patients deal with it.”

So, I began looking into it. My answer could have been, “Because I don’t want to think about that stuff.”

The idea that this disease could dominate my mind (as opposed to taking over my “brain”), among the other things it’s already taken from me, is frightening. And it’s a real possibility.

It is estimated that 50 to 80 percent of people with Parkinson’s disease (PD) will develop dementia. It takes about 10 years from the onset of PD to develop dementia, according to the Alzheimer’s Association.

In those with PD dementia, “plaques” and “tangles” are present. Plaques (not the kind dentist removes from your teeth) are deposits of a type of protein that form around nerve cells. These little monsters begin to cling to one another and form clumps, plaques, which prevent nerve cells from sending messages to each other properly.

Tangles, not the kind you comb out of your hair, are formed of tau protein, found in nerve cells. They are either on their way or have made it to death row. They bunch together, twisting around each other and forming tangles of nerve cell fibers. While tangling up the parallel strands of tau protein nerve cells, they fall apart, disintegrate, and cripple the cells’ communication system.

While this is going on, unawares to the patient, the plaques and the tangles continue to gather inside of the brain, causing other nice and healthy nerve cells to eventually wither away and die a silent death, leading to shrinkage in the area of the brain in which these little monsters had their fun fest.

Plaques and tangles present further complications in people with Parkinson’s, as these are the hallmark brain changes linked to Alzheimer’s disease.

I warned you. I told you we didn’t want to think about this stuff. But, unfortunately, it’s a part of the reality of Parkinson’s disease we must be aware of, not so we can worry and fret, but so that we can receive treatment sooner rather than later.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

https://parkinsonsnewstoday.com/2018/12/12/parkinsons-disease-dementia-tangled/

Small Vessel Disease Linked to Severity of Motor Impairment in Parkinson’s Patients, Study Finds

DECEMBER 12, 2018 Jonathan Grinstein

A disorder related to tiny blood vessels in the brain, known as cortical small vessel disease, is directly linked to worsening motor function in Parkinson’s disease, according to a recent study.

An additional association between modifiable vascular risk factors, in particular hypertension, and dementia highlights the need to manage these risk factors in Parkinson’s patients.

The study, “Impact of small vessel disease on severity of motor and cognitive impairment in Parkinson’s disease,” was published in the Journal of Clinical Neuroscience.

Symptoms of Parkinson’s disease can be affected by different risk factors — any attribute, characteristic, or exposure of an individual that increases the likelihood of developing a disorder or injury. Notably, issues with the heart and its blood vessels, or cardiovascular risk factors, have been shown to contribute to greater motor dysfunction in Parkinson’s disease.

In addition, disorders rooted in the brain’s blood vessels, or cerebrovascular pathologies, are linked with an increased prevalence of parkinsonian symptoms, such as motor dysfunction, and cognitive impairment in the elderly.

The relationship among cortical small vessel disease — an umbrella term covering a variety of abnormalities related to small blood vessels in the brain — cognitive decline, and dementia is well-established. Despite this, small vessel disease is not considered a significant cause underlying cognitive impairment in Parkinson’s, and it is not clear whether and to what extent its symptoms and progression contribute to Parkinson’s motor severity and cognitive impairment.

Some of the most concrete evidence for understanding the impact of comorbidities — the simultaneous presence of two chronic diseases or conditions in a patient — in Parkinson’s and other neurodegenerative diseases has been obtained through autopsies of patients’ brains.

By comparing the clinical information collected from patients, such as motor function and cognitive ability, during treatment with an autopsy report, doctors can better assess the link among risk factors, the course of Parkinson’s disease, and the severity of parkinsonian symptoms and dementia.

Cerebrovascular disease pathologies, such as small vessel disease, have only been assessed in a limited number of autopsy studies of Parkinson’s patients.

Now, researchers at the University of Sydney Medical School in Australia have studied the relationship among vascular risk factors and small vessel disease and the severity of motor impairment, cognitive dysfunction, and dementia in Parkinson’s patients. Vascular risk factors studied included stroke, heart disease, hypertension, diabetes, and cigarette smoking.

To do so, they examined clinical information from 77 autopsy-confirmed Parkinson’s patients who were similar in age, cause of death, and duration or severity of Parkinson’s disease.

The researchers then examined clinical information collected during patient visits to determine the severity of cognitive dysfunction and motor impairment. The severity of motor impairment and disease progression was determined using the Hoehn and Yahr scale, while the Clinical Dementia Rating was used to assess the severity of cognitive dysfunction and progression.

Of the 77 patients, 65 percent had advanced-stage dementia. The mean duration of Parkinson’s disease was 12 years for patients with and without dementia. Patients with dementia had more vascular risk factors than those without dementia, including stroke, heart disease, hypertension and diabetes, and a longer history of cigarette smoking.

Researchers observed that the severity of small vessel disease was related to the degree of motor impairment. They did not find a link between the severity of small vessel disease and the presence of dementia in these patients.

They also found a link between the severity of modifiable vascular risk factors and cognitive impairment in the autopsies of Parkinson’s patients. Among the vascular risk factors, only hypertension was linked with cognitive impairment and dementia.

“Modifiable vascular risk factors relate most to the severity of cognitive rather than motor impairment in Parkinson’s disease,” the researchers wrote. This emphasizes the importance “of a holistic approach to the treatment of PD  [Parkinson’s disease] including the potential for longterm cognitive benefits of early and aggressive management of vascular co-morbidities.”

“Our study suggests that neurologists treating patients with Parkinson’s disease should proactively manage their patient’s vascular risk factors, which may reduce gait and cognitive impairment, two of the main clinical features that undermine well-being and independence in patients with Parkinson’s disease,” lead study author Jillian Kril, PhD, said in a news article published in Neurology Today.

https://parkinsonsnewstoday.com/2018/12/12/small-vessel-disease-linked-motor-function-decline-parkinsons-study/

Defective Activity of GCase Enzyme Linked with Neurodegeneration in Parkinson’s, Mouse Study Finds

 DECEMBER 12, 2018 BY JOSE MARQUES LOPES, PHD 

Impaired activity of the enzyme glucocerebrosidase (GCase), which is responsible for breaking down and recycling cell waste, boosts neurodegeneration and accumulation of alpha-synuclein in Parkinson’s, according to a new mouse study.

The research, “Development and biochemical characterization of a mouse model of Parkinson’s disease bearing defective glucocerebrosidase activity,” was published in the journal Neurobiology of Disease.

Mutations in both copies (homozygous) of the GBA1 gene are responsible for the development of Gaucher disease, a disorder characterized by impaired activity of GCase — an enzyme responsible for the breakdown of a lipid, called glucosylceramide, inside cells.

If occurring in only one gene copy (heterozygous), mutations in GBA1 do not cause Gaucher, but are considered the most relevant risk factor for Parkinson’s after reaching advanced age. Nearly 10 percent of patients with sporadic Parkinson’s disease have heterozygous GBA1 mutations, showing more severe cognitive decline and a slightly younger age of onset compared to those without such mutations.

A link between the hallmark Parkinson’s protein alpha-synuclein and GCase has been suggested by the observation of a mutant form of this enzyme in Lewy bodies (protein clumps mainly formed by aggregates of alpha-synuclein). Also, prior studies have shown that inhibiting GCase activity boosts alpha-synuclein accumulation and activation of cells called microglia, a sign of neuroinflammation seen in patients with Parkinson’s disease.

Researchers at the IRCCS Mondino Foundation, in Italy, aimed to better understand the association between GCase deficiency and Parkinson’s. Specifically, they explored whether a partial defect in GCase comparable to that caused by heterozygous mutations in GBA1 (with approximately 50 percent of residual GCase activity) may increase the effects of MPTP, a widely used neurotoxin to cause Parkinson’s in animal models.

The team developed a model with partial deficiency of GCase activity caused by chronic (28 days) administration of low doses of CBE — a GCase inhibitor — in mice injected with MPTP for five days.

They then determined brain GCase activity, degeneration of dopamine-producing neurons in the nigrostriatal pathway, alpha-synuclein levels, and neuroinflammation. Of note, progressive degeneration of the brain’s nigrostriatal pathway — one of the four major dopamine pathways in the brain, involved in production of movement — is a characteristic event in Parkinson’s.

The results showed that a CBE dose of 50 mg/kg of body weight caused GCase activity reduction in the cerebral cortex similar to that seen in Parkinson’s patients with heterozygous GCase mutations.

The team then found that, although not statistically significant, pre-treatment with this CBE dose boosted MPTP-induced neurodegeneration in the striatum. This was assessed by the amount and signal of tyrosine hydroxylase — the enzyme that mediates the production of the dopamine precursor L-DOPA — as well as by the number of neurons containing this enzyme.

“Our results confirm the concept that GCase dysfunction renders nigrostriatal neurons more susceptible to neurodegeneration,” researchers wrote.

Also, using both CBE and MPTP was able to cause a significant increase in the number of dopamine-producing neurons expressing alpha-synuclein in the substantia nigra, leading to the initiation of the process of alpha-synuclein primary aggregation. Of note, the substantia nigra is a brain region that contains dopaminegic neurons, which are lost as a consequence of Parkinson’s disease.

In turn, microglia was markedly activated by either CBE or MPTP within the substantia nigra. Co-administration of these two compounds did not promote further activation, which the investigators attributed to all microglia cells already being activated by each compound separately.

“Overall, we believe this model may be used as an additional tool to study the biochemical processes underlying pathophysiology [changes of normal physiological functions associated with disease] characterizing [Parkinson’s] in the presence of GCase defects,” researchers wrote.

https://parkinsonsnewstoday.com/2018/12/12/gcase-dysfunction-linke3d-neurodegeneration-parkinsons-study/

A lipid-desaturating enzyme offers a new drug target for Parkinson’s disease

by Ryan Cross     DECEMBER 10, 2018

Two teams of scientists independently discovered that inhibiting an enzyme called stearoyl-CoA desaturase reduces the toxicity of α-synuclein, a protein implicated in Parkinson’s disease

Credit: Yumanity Therapeutics

Two teams used yeast to identify a new drug target for Parkinson's disease. The image shows α-synuclein-expressing yeast (white cells) superimposed over cortical neurons (green). Nuclei are shown in blue, and structures called the Golgi apparatus are shown in red.

Two teams of researchers have independently converged on a new drug target for Parkinson’s disease. Two studies published last week, one from the biotech start-up Yumanity Therapeutics and another led by the lab of Dennis J. Selkoe at Brigham and Women’s Hospital and Harvard Medical School, both discovered that small-molecule inhibitors of a fatty acid–metabolizing enzyme could alleviate the toxic effects of a protein implicated in the neurodegenerative disease.

Despite decades of research, scientists still don’t fully understand what causes Parkinson’s disease. One culprit is a protein called α-synuclein. The protein hangs around the lipid membranes of cells, but it’s not entirely clear what its normal function is. In Parkinson’s, misfolded forms of α-synuclein form toxic clumps inside brain cells, and rare genetic mutations that increase α-synuclein levels are linked to inherited forms of the disease. This has made reducing α-synuclein a popular strategy for drug developers.

α-Synuclein’s floppy, unstructured form has made it difficult to target with standard small molecule drugs, so most ongoing drug programs target the protein with antibodies. But these experimental antibody therapies face two big hurdles: Antibodies struggle to enter the brain and to slip into cells, where α-synuclein clusters. “There’s been virtually no handle on how you would treat the disease with a small-molecule therapy,” Selkoe says.

The studies from Yumanity and Selkoe present a new, unexpected way to reduce toxic α-synuclein levels with a small molecule. The two teams concluded that increased levels of a monounsaturated fatty acid called oleic acid, found in cell membranes, aggravates α-synuclein’s toxicity. Using small molecule compounds to inhibit the activity of an enzyme called stearoyl-CoA desaturase (SCD), which makes oleic acid, eliminates α-synuclein’s toxic effects in cells. The strategy is totally different from any other intervention ever attempted for Parkinson’s disease, and Yumanity plans to test the idea in humans by the end of next year.

“This is an exciting development in the field of α-synuclein therapeutics and Parkinson’s disease,” says Subhojit Roy, a neuroscientist at the University of Wisconsin who was not involved in the study. He is also encouraged that two papers, with different approaches, arrived at the same target. “While the effect of α-synuclein on lipids has been known for some time, therapeutic strategies exploiting this property have been few and far in between,” he adds.

Both groups started by using yeast to uncover the link between SCD and α-synuclein. Yumanity, a biotech startup that raised $45 million in 2016, was founded on the idea that yeast could provide a quick way to find new targets and therapies for neurodegenerative diseases. Their program targeting SCD “is the first publicly disclosed output of that discovery engine,” says Chief Scientific Officer Kenneth Rhodes.

Yeast don’t normally make α-synuclein, so scientists at Yumanity introduced the human gene for the protein into yeast cells. As the cells produce the protein, it impedes their growth. This fact allowed the team to set up an easy-to-follow screen in which the researchers exposed the yeast to a library of small molecules to find a compound that allowed the cells to grow in the presence of the toxic α-synuclein. A collection of compounds containing a core 1,2,4-oxadiazole structure rescued the yeast from the α-synuclein toxicity and reduced the protein’s aggregation in the cells (Cell Rep. 2018, DOI: 10.1016/j.celrep.2018.11.028).

Next, the team had the more arduous task of figuring out what their best-performing oxadiazole compound was doing inside the cells. Yumanity looked for yeast that weren’t rescued by the compound, indicating that the cells carried a mutation that prevented the compound from working. The team found several such mutant yeast, all of which had mutations in a gene called OLE1. The human equivalent of OLE1 is SCD1, which encodes a variant of the SCD enzyme.

The second study, led by Selkoe, reached similar conclusions about SCD. Parts of the study were also completed in the lab of Susan Lindquist, former director of the Whitehead Institute for Biomedical Research, who died in 2016. Lindquist developed yeast-screening methods that were exclusively licensed to Yumanity.

The Selkoe and Lindquist team started by expressing human α-synuclein in yeast to see how its expression altered the cells’ lipid profile. They observed increases in unsaturated fatty acids, particularly oleic acid. Directly adding oleic acid to cells intensified α-synuclein toxicity, and lowering levels of the oleic acid–making enzyme Ole1 relieved α-synuclein toxicity.

Next the group tested the effects of reducing oleic acid in rat and human neurons grown in a lab, a Parkinson’s worm model, and a Parkinson’s mouse model. In all cases, the enzyme that makes oleic acid—SCD in humans—emerged as a promising drug target for reducing α-synuclein toxicity (Mol. Cell 2018, DOI: 10.1016/j.molcel.2018.11.028).

“The results are pretty dramatic,” but not a complete surprise, says Robert Edwards, a neuroscientist whose lab is studying α-synuclein at University of California, San Francisco. Lindquist showed that α-synuclein interacts with cell membranes 15 years ago, he says. “That interaction becomes even more clear and prominent as time goes by.”

The papers, although promising, raise several questions, Edwards says, such as why α-synuclein expression would raise oleic acid levels. “Synuclein by itself seems to do something to membranes, but it’s not clear why it does that or what it means,” Edwards says. Selkoe says his lab is investigating these questions.

Edwards adds that blocking SCD could alter the lipid composition of cells throughout the body. The consequences of that are not known, but Yumanity thinks the strategy should be safe because drug companies have already studied SCD inhibitors as antiobesity drugs. Those drugs never made it to market because they were not effective for weight loss, but Yumanity’s Rhodes notes that there were no safety concerns in clinical trials of the drug.

Yumanity plans to test a drug candidate called YTX-7739 in a Phase I clinical trial next year. The startup isn’t disclosing the structure of this compound, but Rhodes says it is chemically distinct from the oxadiazole compounds presented in their paper. The compound was also designed to target a variant of SCD called SCD5, expressed primarily in the brain and more strongly than SCD1, which is found throughout the body.

Time will tell if this approach will have more success than programs targeting α-synuclein directly, which are in early-to-mid-stage clinical trials. The new strategy has “a rationale, and a lot of things tried in Parkinson’s disease have a pretty weak rationale,” Edwards says. “It has to do with synuclein, so it’s getting close to the heart of the matter.”

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