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Awakening Dormant Neurons Could Provide Disease-modifying Parkinson’s Treatment, Early Study Suggests

dormant neurons

Together with dying nerve cells, dormant neurons also may be at the root cause of Parkinson’s disease, according to a recent study in animal models.

Reawakening these neurons by targeting a type of brain cells called astrocytes can restore dopamine production in the brain and reverse Parkinson’s motor symptoms, the study found. These findings could lead to a potential new disease-modifying treatment, especially at the early stages of Parkinson’s.

The study, “Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease,” was published in the journal Current Biology.

Despite its prevalence and debilitating consequences, current medical therapy for Parkinson’s relies on alleviating symptoms. Research investigating ways of modifying the disease or reversing its symptoms is scarce, based on the firm belief that Parkinson’s is caused by the irreversible death of nerve cells — also called neurons — in a region of the brain called the substantia nigra.

In this brain region, nerve cells known as dopaminergic neurons are responsible for producing the neurotransmitter dopamine, a chemical messenger that allows nerve cells to communicate. Dopamine plays a key role in motor function control and also is involved in behavior and cognition, memory and learning, sleep, and mood.

Levodopa, a mainstay of Parkinson’s treatment, works by supplying extra dopamine to the brain. However, it only alleviates motor symptoms and does not alter the disease course. Moreover, its long-term use can cause serious side effects, including involuntary, erratic, and writhing movements.

Now, a team of Korean researchers have discovered additional clues about the underlying mechanisms of Parkinson’s that may offer hope for the development of disease-modifying treatments that could reverse the condition.

Using mouse and rat models of Parkinson’s, they found that the motor abnormalities that mark the disease begin earlier than was previously thought. They are triggered when dopaminergic neurons in the substantia nigra are still alive but in a dormant state, unable to produce dopamine.

However, what holds the key to that dormant state is another type of cells called astrocytes, star-shaped cells present in the brain and spinal cord that play important roles in the protection and regulation of the nervous system.

When neurons die, nearby astrocytes react by proliferating, and start to release an inhibitory neurotransmitter called gamma-aminobutyric acid (GABA) at excessive levels. This puts neighboring neurons “on hold,” suspending their production of dopamine.

GABA prevents the neurons from firing electrical impulses and causes them to stop making an enzyme, called tyrosine hydroxylase, that’s essential for the production of dopamine. In effect, GABA puts the neurons into a dormant, or sleeping state.

One of the most important discoveries of the study was that surviving dormant neurons could actually be “awakened” from their “sleeping” state and rescued to alleviate motor symptoms.

“Everyone has been so trapped in the conventional idea of the neuronal death as the single cause of PD. That hampers efforts to investigate roles of other neuronal activities, such as surrounding astrocytes,” C. Justin Lee, PhD, the study’s corresponding author, said in a press release.

“The neuronal death ruled out any possibility to reverse PD. Since dormant neurons can be awakened to resume their production capability, this finding will allow us to give PD patients hopes to live a new life without PD,” Lee added.

Treatment with two different compounds that block GABA production in astrocytes, called monoamine oxidase-B, or MAO-B, inhibitors, was sufficient for neurons to recover the enzymatic machinery necessary to produce dopamine, the study found. This significantly alleviated Parkinson’s motor symptoms in the study animals.

In fact, the MAO-B inhibitors used for the study — selegiline (brand names EldeprylCarbex, Zelapar, among others), and safinamide (brand name Xadago) — are already prescribed to Parkinson’s patients as an add-on therapy to levodopa. They are believed to prevent the break down of dopamine in the brain.

Importantly, the existence of dormant neurons was observed in the brains of human patients. Analysis of postmortem brains of individuals with mild and severe Parkinson’s had a significant population of dormant neurons surrounded by numerous GABA-producing astrocytes.

The researchers hope that “awakening” neurons using MAO-B inhibition could be an effective disease-modifying therapeutic strategy for Parkinson’s, especially for patients in the early stages of the disease. At that time, inactive, yet live dopaminergic neurons are still present.

Although the results from several clinical trials have cast doubt on the therapeutic efficacy of traditional MAO-B inhibitors, researchers say they have recently developed a new inhibitor, KDS2010. KDS2010 effectively inhibits astrocytic GABA production with minimal side effects in Alzheimer’s animal models and also could be effective for alleviating Parkinson’s motor symptoms, the investigators said.

“This research refutes the common belief that there is no disease-modifying treatment for PD due to its basis on neuronal cell death,” said Hoon Ryu, PhD, a researcher at KIST Brain Science Institute, in South Korea, and one of the senior authors of the study.

“The significance of this study lies in its potential as the new form of treatment for patients in early stages of PD,” Ryu said.

The fact that inhibition of dopaminergic neurons by surrounding astrocytes is one of the core causes of Parkinson’s should be a “drastic turning point” in understanding and treating not only Parkinson’s but also other neurodegenerative diseases, added Sang Ryong Jeon, MD, PhD, also a researcher at KIST and a study co-author.

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Excess Iron in Brain Cells Worsens Parkinson’s Symptoms, Mouse Study Shows

excess iron in brain

While excess iron in the brain often accompanies Parkinson’s disease, it remains unknown whether the iron overload actually causes the neurodegenerative disorder or is merely a product of it.

New research now sheds greater light on the role that iron plays in the development of a Parkinson’s disease model. It also illustrates how certain cells regulate the brain’s response to changing iron levels.

The study, entitled “Iron overload induced by IRP2 gene knockout aggravates symptoms of Parkinson’s disease,” was published in the journal Neurochemistry International.

Iron regulatory protein 2 (IRP2), a gene involved in iron metabolism, responds to low levels of cellular iron in the brain. It acts through two other genes, TfR1 and DMT1, to increase iron uptake by cells. Conversely, when IRP2 senses an increase in intracellular iron, it acts to limit iron storage within cells.

Because of IRP2‘s critical role in iron homeostasis, or the balance of iron within the body, a group of researchers from Heibei Normal University in Shijiazhuang, China, asked whether a Parkinson’s disease model could be induced when IRP2 was not present.

The team treated mice that lacked IRP2 with a compound called MPTP, a chemical commonly used to create models of Parkinson’s in mice. MPTP crosses the blood-brain barrier (BBB), where it is toxic to the dopamine-producing (dopaminergic) neurons of the substantia nigra (SN), a brain region severely affected during the course of Parkinson’s. The death of dopaminergic neurons is one of the key features of Parkinson’s disease.

Mice without IRP2 (mutant mice) showed impaired motor skills, compared with their untreated wild-type counterparts. These impairments grew even worse following treatment with MPTP. One of the main tests of motor skills in mice is called the rotarod test, in which a mouse must balance on a rod that rotates around a long axis.

“Most interesting in our experiment, MPTP treatment obviously decreased the amount of time staying on the rotarod for both [wild-type] and IRP2 mice,” the researchers said.

The MPTP-treated mutant mice accumulated more iron in their substantia nigra and lost more dopaminergic neurons in the SN than any other group of mice. Treating the mutant mice with MPTP also changed the gene expression of TfR1 and DMT1, which assist IRP2 in regulating cellular iron. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

The researchers suspect that these genetic changes in TfR1 and DMT1 cause the abnormal iron storage.

MPTP treatment in mutant mice caused changes in iron metabolism not only in dopaminergic neurons, but also in astrocytes, specialized neural cells that protect other neurons from damage, the researchers found. Several studies have linked abnormal astrocyte behavior to the development of Parkinson’s.

In this study, iron-laden astrocytes were less able to protect dopaminergic neurons from the effects of the chemicals used to trigger the Parkinson’s mouse model.

This new research does not answer the question of whether excess iron in the brain can cause Parkinson’s, the researchers noted. However, it does show how such abnormal iron storage contributes to the disease’s progress, and increases scientists’ knowledge of how iron is regulated within the brain.

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Abnormal Brain Cell Type Leads to Parkinson’s-Related Neurodegeneration, Study Contends

brainstem cells

Scientists have found that an abnormal version of brain cells called astrocytes contribute to the accumulation of alpha-synuclein protein, the main component of Parkinson’s disease hallmark Lewy bodies.

Their study, “Patient-specific iPSC-derived astrocytes contribute to non-cell autonomous neurodegeneration in Parkinson’s disease,” was published in Stem Cell Reports.

Parkinson’s disease is linked to degeneration of the ventral midbrain (relating to the inferior part of the brain), a region that houses dopamine-releasing neurons.

Post-mortem analysis of Parkinson’s disease brain tissue has revealed astrocytes accumulate toxic amounts of alpha-synuclein during the disease process. Research also suggests that this toxic protein can be taken up and spread from astrocytes to neurons, causing neuronal death.

Astrocytes are star-shaped cells that outnumber neurons by fivefold. Found in the central nervous system, astrocytes are known as housekeeping cells because they care for neurons, nurture them and “clean up” after them.

Investigators set up to further investigate a role for Parkinson’s disease-related astrocyte dysfunction in midbrain nerve cell death.

They generated astrocytes and ventral midbrain dopaminergic neurons from induced pluripotent stem cells (iPSCs) of healthy individuals and of patients with the LRRK2 G2019S mutation, the most commonly found mutation in Parkinson’s disease.

iPSCs are derived from either skin or blood cells that have been reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of almost any type of human cell needed.

Although LRRK2’s main function is not known, it seems to play a key role in mitochondria — cells’ powerhouses — namely in autophagy, a process that allows cells to break down and rebuild their damaged components.

Healthy neurons and Parkinson’s astrocytes were together in the same lab dish to study their cellular interactions. Results revealed a significant decrease in the number of healthy ventral midbrain dopaminergic neurons when cultured together with Parkinson’s disease astrocytes, which was associated with astrocyte-derived alpha-synuclein aggregation.

Healthy neuronal death was caused by the shortening and disintegration of the cells’ projecting branches, known as axons and dendrites.

When healthy astrocytes were cultured with Parkinson’s neurons, the housekeeping cells partially prevented the appearance of disease-related cellular changes and alpha-synuclein buildup in the diseased neurons.

“We found Parkinson’s disease astrocytes to have fragmented mitochondria, as well as several disrupted cellular degradation pathways, leading to the accumulation of alpha-synuclein,” the study’s co-first author Angelique di Domenico, PhD, said in a press release.

Because Parkinson’s astrocytes had high levels of alpha-synuclein in them, researchers hypothesized that the toxic protein could be transferred to healthy dopamine-producing neurons and cause the damage they had previously observed.

Using the CRISPR-Cas9 gene editing tool, the team generated two new astrocyte lines (representing one Parkinson’s patient and one healthy control). This allowed them to “tag” alpha-synuclein within living cells and track the protein as it was generated by astrocytes and transferred to dopamine-producing neurons.

As expected, alpha-synuclein in Parkinson’s astrocytes accumulated at abnormally high levels and, upon culture with healthy dopamine-producing neurons, a direct transfer of astrocytic alpha-synuclein to neurons was observed.

Researchers then used this gene-editing technology to generate Parkinson’s astrocytes that lacked the LRRK2 G2019S mutation. Abnormal alpha-synuclein accumulation did not occur in gene-corrected astrocytes and upon culture with healthy neurons, there was no accumulation of alpha-synuclein or decrease in neuron survival.

Researchers then treated Parkinson’s astrocytes with a chemical designed to correct the cells’ disrupted clean-up system.

“We were elated to see after treatment that the cellular degradation processes were restored and alpha-synuclein was completely cleared from the Parkinson’s disease astrocytes,” di Domenico said. “These results pave the way to new therapeutic strategies that block pathogenic interactions between neurons and glial cells.”

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Compound Similar to Diabetic Medications Slows Parkinson’s Progression in Mouse Study

mice movement brain

An investigative compound similar to those used to treat diabetes was able to slow Parkinson’s progression and ease behavioral symptoms associated with the disease in mouse models.

The compound, called NLY01 and developed by scientists at Johns Hopkins Medicine, works to protect against the loss of dopaminergic nerve cells — directly targeting a cause of Parkinson’s progression — and may enter clinical testing this year.

The study, “Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease,” was published in Nature Medicine.

NLY01 binds to a specific type of receptors, called glucagon-like peptide-1 receptors, found on pancreas cells. Similar medications, such as Byetta (exenatide, by AstraZeneca) and Victoza (liraglutide, Novo Nordisk), treat type 2 diabetes by increasing blood insulin levels.

Although prior studies in animal models suggest these medications are neuroprotective in ways that might benefit Parkinson’s and Alzheimer’s patients, how these compounds act in the brain was not known.

Researchers tested NLY01 on three key cell types in the human brain — neurons, astrocytes, and microglia. While astrocytes mediate such processes as nerve cell communication and control of the blood-brain barrier (a permeable membrane that protects the brain), microglia are crucial in immune responses to infection or injury.

The team found microglia contained the greatest number of receptors that NLY01 can bind to: twice those of the other two cells.   These receptors are also 10 times higher in Parkinson’s patients than in individuals without the disease.

Microglia, the researchers knew from other work, produce chemical signals that change astrocytes into overactive and aggressive cells that damage nerve cell connections and eventually kill neurons.

“The activated astrocytes we focused on go into a revolt against the brain,” Ted Dawson, a study co-author and a professor of neurology at Johns Hopkins, said in a press release.

“This structural breakdown contributes to the dead zones of brain tissue found in those with Parkinson’s disease. The idea was that if we could find a way to calm those astrocytes, we might be able to slow the progression of Parkinson’s,” he added.

Treating laboratory-grown human brain cells with NLY01 switched off  the damaging signals initiated by microglia. When healthy astrocytes were combined with treated microglia, they did not convert into aggressive and toxic cells.

Dawson’s team then injected NLY01 into mice engineered to have abnormal alpha-synuclein protein, the major component of protein clumps known as Lewy bodies, and a hallmark of Parkinson’s.

While untreated mice showed marked motor problems in behavioral tests done over six months, those given NLY01 had normal physical function and no loss of dopamine-producing neurons, another Parkinson’s hallmark.

NLY01 treatment in the disease model mice prolonged their lifespan by more than 120 days, and eased behavioral problems and evidence of neurodegeneration.

“It is amazingly protective of target nerve cells,” Dawson said.  NLY101 was also more effective at crossing the brain-blood barrier — essential to treating diseases of the brain —  than related diabetes medications.

“In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson’s disease and related neurologic disorders characterized by microglial activation,” the researchers wrote.

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Source: Parkinson's News Today

Neurodegenerative Disease Mechanisms May Begin Soon After Birth, Mouse Study Suggests

Early disease mechanisms

The mechanisms that lead to progressive degenerative diseases like Parkinson’s in adulthood begin much earlier than previously thought, a mouse study suggests.

In fact, they may start soon after birth, researchers said.

The study, “Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1,” was published in the Journal of Clinical Investigation.

A movement disorder called spinocerebellar ataxia type 1 (SCA1) is caused by mutations of the ATXN1 gene. It starts with coordination and balance problems and progresses over time. Symptoms typically begin in early adulthood but can appear any time between childhood and late adulthood.

Northwestern University researchers wondered when the disease’s mechanisms begin appearing. For their study they genetically engineered a mouse to mirror the human disease.

A key thing they discovered was that altered circuitry in the cerebellum — an area of the brain responsible for movement control — sets the stage for later susceptibility to the disease.

The mice lacked the ATXN1 gene. Although their disease’s symptoms appeared relatively late, their brain starting showing alterations in gene activity as early as a week 
after birth.

“Given the importance of this postnatal period for cerebellar development, we asked whether this region might be developmentally altered by mutant 
ATXN1,” the researchers wrote.

They focused on stem cells in cerebellar white matter that play key roles in the animals’ first weeks of life. The stem cells differentiate into important nerve cells — basket cells and stellate cells.

Importantly, the stem cells also give rise to cerebellar astrocytes, star-shaped cells that regulate the connections between nerve cell signaling and central nervous system blood vessels.

ATXN1 gene mutations increase the proliferation of cerebellar stem cells and influence their fate, researchers said. They way they do this is by promoting the stem cells’  differentiation into nerve cells and away from an astrocyte lineage.

“We were amazed to find that they multiplied excessively and tended to differentiate into inhibitory neurons called basket cells,” Puneet Opal, MD, PhD, a professor at Northwestern University Feinberg School of Medicine, said in a press release.

“We knew that cerebellar stem cells generate inhibitory neurons [one class of nerve cell], but in this case the number of inhibitory neurons was so much more than normal that they generated an enhanced inhibitory effect on Purkinje neurons, the chief output neurons of the cerebellum,” said Opal, who was the study’s lead author.

The changes disrupt the normal cerebellar function, he said. “This network dysfunction could be a constant stress, and that constant stress makes the neural network deteriorate over time,” he added.

While the mechanisms underlying the detrimental effects of mutant ATXN1 remain unknown, the findings point to an underappreciated phenomenon: The mechanisms of neurodegenerative diseases begin very early in life, before symptoms appear.

“This is the first discovery of alterations in an adult-onset spinocerebellar disorder that stem from such early developmental processes,” Opal said. “This may well be generalizable to a whole host of other diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.”

 

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Source: Parkinson's News Today