Scientists Uncover New Therapeutic Molecule BT13 That May Possibly Protect Against Neurodegeneration

therapeutic molecule BT13

Scientists have uncovered a new therapeutic molecule, called BT13, that can get to the brain to boost dopamine levels — the brain chemical that’s in short supply in Parkinson’s disease — and could potentially protect against neurodegeneration.

While the research is in the early stages, and the molecule has only been tested in mice and cellular models of the disease, the researchers say BT13 shows promise as a way to slow or stop Parkinson’s instead of just treating its symptoms.

The findings were described in the study, “Glial cell line–derived neurotrophic factor receptor Rearranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo,” published in Movement Disorders.

Evidence shows that a small protein known as glial cell line-derived neurotrophic factor, or GDNF, supports the growth, survival, and differentiation of dopaminergic neurons — those that produce dopamine and progressively degenerate in Parkinson’s disease.

In animal models of Parkinson’s, as well as in human clinical trials, GDNF has shown neuroprotective effects.

However, due to its large size, GDNF is not able to cross the human blood-brain barrier (BBB), and complex surgery is required to deliver the treatment to the brain. The BBB is a semipermeable membrane that protects the brain against the external environment, but is a major barrier for the efficient delivery of therapies that need to reach the brain and central nervous system to work.

BT13, another molecule that binds the same signaling receptor — or RET receptor — for the GDNF molecule family, is much smaller in size than GDNF. Researchers say BT13 has the potential to produce the same neuroprotective effects as GDNF and should be able to more easily cross the blood-brain barrier.

Now, a team of scientists from the University of Helsinki in Finland set out to study this small molecule’s effects in immortalized nerve cells — neurons that are engineered to proliferate indefinitely — and in live mice.

The results revealed that after binding to RET, BT13 triggered molecular signaling cascades related to cellular survival and growth in normal dopamine-producing immortalized neurons. However, when cells were engineered to lack the RET receptor, BT13 had no effect.

BT13 was found to protect against Parkinson’s-related neurodegeneration, which was simulated in the lab by exposing dopaminergic neurons in dishes to 6-OHDA and MPP+ — both neurotoxins that induce cell death and mimic disease symptoms. Importantly, BT13 only protected these neurons when they expressed the RET receptor.

In addition, when BT13 was administered to mice — through an injection directly into the brain — it was able to cross the blood-brain barrier. When in the brain, the molecule activated cell survival and growth pathways and promoted the release of dopamine from the animals’ striatum, a motor control brain area primarily affected by Parkinson’s.

“People with Parkinson’s desperately need a new treatment that can stop the condition in its tracks, instead of just masking the symptoms. One of the biggest challenges for Parkinson’s research is how to get drugs past the blood-brain barrier, so the exciting discovery of BT13 has opened up a new avenue for research to explore, and the molecule holds great promise as a way to slow or stop Parkinson’s,” David Dexter, PhD, deputy director of research at Parkinson’s UK and professor of neuropharmacology at Imperial College London, said in a press release.

“We are constantly working on improving the effectiveness of BT13,” said Yulia Sidorova, PhD, the study’s lead researcher. “We are now testing a series of similar BT13 compounds, which were predicted by a computer program to have even better characteristics.

“Our ultimate goal is to progress these compounds to clinical trials in a few coming years,” Sidorova said.

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Activated Immune T-Cells Infiltrate the Brain and Promote Neurodegeneration in Primate Models of Parkinson’s

Activated Immune T-Cells

Activated immune T-cells can infiltrate the brain and promote neurodegeneration in non-human primate models of Parkinson’s during the chronic stages of the disease, a study has found.

Results of the study, “Chronic infiltration of T lymphocytes into the brain in a non-human primate model of Parkinson’s disease,” were published in the journal Neuroscience.

Parkinson’s disease is a neurodegenerative disorder 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.

Recent studies have suggested that activated T-cells, which are immune cells that are responsible for destroying other cells or microbes seen as a threat by the immune system, also can play a key role in Parkinson’s neurodegeneration.

Studies in non-human primate models of induced-Parkinson’s have reported the infiltration of these activated T-cells in the brain’s substantia nigra a month after treatment with MPTP during the acute phase of the disease. (MPTP is a neurotoxin that induces brain inflammation and often is used to trigger the onset of Parkinson’s in different animal models.)

“[H]owever, T lymphocyte infiltration into the brain during the chronic phase after MPTP injection in NHP [non-human primate] models remains unclear. We believe that a better understanding of this phenomenon will help identify the neuropathological mechanisms underlying PD [Parkinson’s disease] in humans,” the researchers wrote.

In mice models of the disease, the chemokine RANTES also has been associated with the infiltration of activated T-cells into the brain and with the development of Parkinson’s. (Chemokines are small molecules that mediate and regulate immune and inflammatory responses.)

A team of Korean researchers investigated the mechanisms underlying the infiltration of activated T-cells during the chronic stage of the disease in non-human primate models of induced-Parkinson’s.

In addition to evaluating the infiltration of T-cells in the brain 48 weeks after animals received an injection of MPTP, investigators also assessed changes in the levels of RANTES in the animals’ blood, and assessed microglia activation. (Microglia activation refers to the process by which microglia — nerve cells that support and protect neurons — become overactive, triggering brain inflammation.)

A total of five animals were injected with MPTP and three received a saline injection (controls).

Compared to saline-treated animals, those treated with MPTP showed signs of local chronic infiltration of activated T-cells in different regions of the brain’s striatum — a brain region responsible for controlling body movements — and substantia nigra.

Moreover, in animals treated with MPTP, this was accompanied by the loss of dopaminergic neurons, abnormal microglia morphology, and chronic normalization of the levels of RANTES in the blood 24–48 weeks post-injection, indicative of inflammation.

“This study confirms the involvement of [T-cell] infiltration in MPTP-induced NHP [non-human primates] models of PD. Further, these findings reinforce those of previous studies that identified the mechanisms involved in [T-cell]-induced neurodegeneration,” the researchers wrote.

“The findings of chronic infiltration of T lymphocytes in our NHP model of PD provide novel insights into PD pathogenesis and the development of preventive and therapeutic agents,” they stated.

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Neurofilament Light Chain Levels May Be Useful Biomarker for Disease Progression in Parkinson’s, Study Finds

Neurofilament light chain

Levels of neurofilament light chain (NfL) — a protein found in blood plasma — may be a useful biomarker of disease progression for Parkinson’s, a study says.

The study, “Blood NfL: A biomarker for disease severity and progression in Parkinson disease,” was published in the journal Neurology.

A hallmark feature of Parkinson’s disease is the progressive degeneration of brain cells, which can happen at varying rates in different people. As such, researchers have focused on discovering a biomarker of neurodegeneration that could be used to predict the course of the disease for each individual patient.

The protein neurofilament light chain (NfL) is a key component of axons — myelinated nerve segments responsible for the transmission of nerve signals — and the main byproduct of nerve cell degeneration.

In other chronic neurodegenerative disorders — including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inherited peripheral neuropathy, Alzheimer’s dementia, and frontotemporal dementia — studies have reported that the levels of NfL in blood plasma were abnormally high, suggesting its usefulness as a marker of neurodegeneration.

In the case of spinal muscular atrophy (SMA), a genetic neurodegenerative disorder that affects motor neurons, the phosphorylated neurofilament heavy subunit (pNF-H) — a key component of motor nerve cells — is also being investigated as a potential biomarker of neurodegeneration.

In this study, researchers from the National Taiwan University and their collaborators set out to investigate if plasma levels of NfL could also be associated with disease progression in people with Parkinson’s disease.

To that end, they carried out a prospective longitudinal study in which they followed 116 patients with Parkinson’s, 22 people with multiple system atrophy (MSA) — a rare neurodegenerative disorder — and 40 healthy individuals (controls).

Plasma levels of NfL were measured in all study participants using an electrochemiluminescence immunoassay — a technique that allows researchers to measure the levels of a protein of interest based on an electrochemical reaction. Researchers noted that the testing required just a blood sample from each participant.

Those who had Parkinson’s performed motor and cognitive tests at the beginning of the study, and at a mean follow-up interval of three years. The Unified Parkinson’s Disease Rating Scale (UPDRS) Part III and the Hoehn-Yahr scale were used to evaluate the progression of motor symptoms, while the Mini-Mental State Examination (MMSE) was used to assess the progression of cognitive symptoms.

Results showed that plasma levels of NfL were much higher among those with MSA (35.8 pg/mL), compared with those with Parkinson’s (17.6 pg/mL), and controls (10.6 pg/mL).

However, in patients with Parkinson’s, NfL levels were higher among those who had dementia and among those with severe motor impairments (advanced Hoehn-Yahr stage).

Correlation analyses revealed there was a modest association between NfL levels and UPDRS Part III (motor) scores.

Another statistical analysis performed after a mean follow-up of 3.4 years — and normalized for participants’ age, sex, disease duration and baseline symptoms, or symptoms at the start of the study — revealed that higher levels of NfL at baseline were linked to a higher risk of disease progression in patients with Parkinson’s. This was true for either motor or cognitive symptoms.

“Our results suggested that the plasma NfL level could serve as a noninvasive, easily accessible biomarker to assess disease severity and to monitor disease progression in PD,” the researchers said.

“Future large longitudinal follow-up studies that incorporate other biomarkers such as neuroimages are needed to strengthen the possible prognostic role of blood NfL levels in PD progression,” they added.

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Natural Variant of Vitamin B12 Can Prevent Neurodegeneration in Parkinson’s Preclinical Models

vitamin B12 AdoCbl 5’-deoxyadenosylcobalamin

An active form of vitamin B12 can reduce the effects of dopamine loss in Parkinson’s disease caused by genetic mutations in the LRRK2 gene, a study suggests.

These finding means that this form of vitamin B12 could be used as the basis for developing new therapies for treating Parkinson’s.

The study, “Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection,” was published in Cell Research.

Several studies have shown that overactivation of the LRRK2 enzyme, due to genetic mutations in the LRRK2 gene, is associated with the development of a hereditary form of Parkinson’s disease. But increasing evidence has suggested that this enzyme also may contribute to the progression of sporadic cases of Parkinson’s — ones caused by environmental factors.

Increased activity of the LRRK2 enzyme contributes to the accumulation of toxic alpha-synuclein fibers in dopamine-producing neurons of the substantia nigra — a brain region involved in the control of voluntary movements, and one of the most affected in Parkinson’s disease.

Given its important role, researchers have focused on finding ways to prevent the activity of this enzyme as a strategy for treating this neurodegenerative disorder.

Now, an international team of researchers has found that one natural variant of vitamin B12, called AdoCbl (5’-deoxyadenosylcobalamin), can effectively regulate the activity of the LRRK2 enzyme. AdoCbl is approved by the U.S. Food and Drug Administration.

When tested in experimental cell line models, the team found that AdoCbl could significantly reduce the enzyme’s activity, even when it was genetically modified to carry the G2019S mutation — the most common LRRK2 variant linked to Parkinson’s.

Further analysis confirmed that AdoCbl had the ability to directly bind to LRRK2, changing its three-dimensional structure, and preventing its normal function. This allows AdoCbl to work as a strong inhibitor of the enzyme.

“AdoCbl represents a starting point for the development of a new class of LRRK2 activity modulators for the much-needed treatment of LRRK2-linked pathological conditions such as Parkinson’s disease,” the researchers said.

To explore AdoCbl’s therapeutic potential, the team next administrated it in worms carrying the G2019S mutation. The experiments revealed that AdoCbl treatment could prevent the death of dopamine-producing nerve cells and prevent the manifestation of symptoms associated with neurodegeneration.

Additional analysis also revealed that AdoCbl could prevent neurotoxicity and dopamine deficits in fly and mouse models carrying different LRRK2 mutations associated with Parkinson’s.

Identification of vitamin B12 as a modulator of LRRK2 activity “constitutes a huge step forward because it is a neuroprotective vitamin in animal models and has a mechanism unlike that of currently existing inhibitors,” Iban Ubarretxena, director of the Biofisika Institute and co-author of the study, said in a press release.  Biofisika is  a joint research center of the University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea).

“[This active form of vitamin B12] could be used as a basis to develop new therapies to combat hereditary Parkinson’s associated with pathogenic variants of the LRRK2 enzyme,” he added.

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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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Changes in Innate Immunity, Cell Waste Disposal Process Linked to Loss of Dopaminergic Neurons in Early Study

autophagy, immune response

Together with aging, the disruption of a cell’s waste disposal system and exaggerated immune responses can lead to the progressive loss of dopamine-producing neurons seen in diseases like Parkinson’s, according to new research in fruit flies.

The study, “Hyperactive Innate Immunity Causes Degeneration of Dopamine Neurons upon Altering Activity of Cdk5,” was published in the journal Cell Reports.

Immune responses in the brain may be triggered by pathogens (like microbes) and by its links to autophagy — a cellular process that uses organelles called lysosomes to clear waste products and toxic elements (like protein clumps), serving as the cell’s waste disposal system.

Autophagy is also an alternative route for cell death, and it is implicated in a variety of neurodegenerative diseases. However, whether autophagy favors cell survival or death — and whether it is an early triggering event in neurodegeneration or a “late-acting piece” of the mechanism — remains to be understood.

Aging, the greatest risk factor for most neurodegenerative diseases, impacts immunity and autophagy. But it is not yet known if changes in these processes due to aging have a direct role in neurodegeneration, or simply reflect “a correlation among the processes of normal aging,” the study notes.

Researchers at the National Institutes of Health (NIH) used fruit flies, whose autophagy and innate immunity have significant similarities to those of mammals, to study why immunity is altered during neurodegeneration and whether immune system changes are a cause or a consequence of neuronal dysfunction.

A hyperactive innate immune response has been suggested to impact neurodegeneration and aging in fruit flies. However, some studies found that anti-microbial peptides (AMPs) —  small molecules that are part of the innate immune response — may benefit the aging process. These small molecules also have potent antibiotic activity that can kill bacteria, virus, fungi, or cancer cells.

Altered activity of an enzyme called Cdk5 causes changes in fruit flies that highly resemble neurodegeneration in humans, including the loss of neurons linked to learning and memory, disrupted autophagy, sensitivity to oxidative stress, progressive motor dysfunction, and accelerated aging. Preclinical studies have suggested Cdk5 is important for early brain development and may be associated with diseases like Parkinson’s, amyotrophic lateral sclerosis, and Alzheimer’s.

In this study, researchers found that increasing or decreasing the expression of the activating subunit of Cdk5, called Cdk5-alpha, severely disrupted autophagy. Changes it effected were sufficient to trigger an immune system attack on dopamine-producing neurons — whose loss is a hallmark of Parkinson’s — in the animals. Neuronal death was particularly evident in older flies.

Subsequently, the team found that autophagy disruption caused a hyperactive innate immune response, as shown by increased expression of AMPs. This effect was independent of aging and suggested that “AMP overexpression likely plays a central role in the Cdk5α-associated loss of [dopamine-producing] neurons,” the researchers wrote.

Hyperactivation of the immune system was responsible for the age-dependent death of dopamine-producing neurons. Genetically blocking immune responses — either by reducing the expression of a transcription factor called Rel, or by restoring autophagy by increasing a transcription factor known as Mitf, a key regulator of lysosomal function — prevented the loss of these neurons. (Transcription factors are tiny proteins that regulate protein production.)

“These data reveal a simple, linear, dependent genetic pathway, encompassing both autophagy and innate immunity, which, while rigorously separable from aging, interacts with the effects of aging to lead to the degeneration of [dopamine-producing] neurons,” the scientists wrote.

The similarity of “genes, pathways, and cellular phenotypes” between flies and humans make it “very likely” that the processes revealed in this study “also play a central role in the development and progression of human [neurodegenerative disorders],” they concluded.

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Study Uncovers Molecular Mechanism of Protein Linked to Early-onset Parkinson’s

Parkin protein

A protein called Parkin, which is absent or faulty in many patients with early-onset Parkinson’s disease, helps keep cells alive and reduces the risk of inflammation, according to a recent study.

These results suggest that the protein may be implicated in the development of Parkinson’s, specifically the brain inflammation and loss of neurons associated with the disease. This discovery may support the development of treatments that slow Parkinson’s progression by helping rescue neurons that would otherwise die.

The study, “Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy” was published in the EMBO Journal.

Lack of the PRKN gene, which codes for the Parkin protein, or mutations that result in faulty Parkin protein are known drivers of early-onset Parkinson’s disease.  Understanding how this protein influences cell survival can provide insight on how it works and why its deficiency promotes neurodegenerative conditions such as Parkinson’s.

Now, a team led by researchers at the Walter and Eliza Hall Institute of Medical Research and the University of Melbourne, Australia, investigated the cell-protective role of Parkin and conducted experiments in different cell types grown in the laboratory, engineered to express a normal and functional Parkin protein or mutant versions associated with Parkinson’s disease.

The results showed that Parkin was able to block cell death by inhibiting a protein called BAK.

BAK and a related protein, called BAX, are activated in response to cellular damage, setting up a programmed cellular death cascade referred to as apoptosis.

An important part of this process is the dismantling of mitochondria, structures that supply energy to cells. Damage to mitochondria may itself trigger apoptosis and inflammation, warning neighboring cells of a potential danger.

In these conditions, Parkin tags BAK with a small protein called ubiquitin that signals cells to limit BAK’s activity. Ubiquitin is part of a “quality control” system by which cells dispose of damaged, misshapen, or excess proteins.

By suppressing BAK,  Parkin halts cell death and promotes clearance of damaged mitochondria, limiting their potential for inducing inflammation.

“Parkin ‘buys time’ for the cell, allowing the cell’s innate repair mechanisms to respond to the damage,” Grant Dewson, Ph.D., associate professor at the Walter and Eliza Hall Institute and senior author of the study, said in a press release.

“In a healthy brain, Parkin helps keep cells alive, and decreases the risk of harmful inflammation by repairing damage to mitochondria,” said study author Jonathan Bernardini.

The data showed that without Parkin or with faulty variants of it, BAK is not tagged and excessive cell death can occur. This may contribute to nerve cell loss typical of Parkinson’s disease, researchers said.

“Drugs that can stifle BAK, mimicking the effect of Parkin, may have the potential to reduce harmful cell death in the brain,” Dewson said. 

These insights expanded on the knowledge of how neuron death and brain inflammation may occur in Parkinson’s disease. This might help foster new therapies to slow the progression of the disease.

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Deterioration of Nerve Cell Structure Not the Main Cause of Early Parkinson’s Symptoms, Mouse Study Suggests

neuron structure changes

Although the structure of dopaminergic neurons gradually deteriorates before cell death, these alterations do not seem to account for the subtle impairments seen during the early stages of Parkinson’s disease, a mouse study has found.

The study, “Progressively Disrupted Somatodendritic Morphology in Dopamine Neurons in a Mouse Parkinson’s Model,” was published in Movement Disorders.

Parkinson’s is a progressive neurodegenerative disorder caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control.

Previous studies in animal models have shown that neuron dysfunction and cell death start to occur before animals display noticeable motor symptoms associated with Parkinson’s. However, the precise morphological (structural) and functional changes that occur in neurons at this early stage of disease are still not very well understood.

Researchers from the University of Texas Health used a mouse model of adult-onset parkinsonism that perfectly mirrors “the slow, progressive course of Parkinson’s seen in the majority of patients,” according to the study.

These mice, called MitoPark, lack the mitochondrial transcription factor A (TFAM) gene specifically in dopaminergic neurons. As a result, at 12 weeks of age, they show a marked decrease of brain innervation in the striatum — a region responsible for motor coordination — followed by neuron cell death at 30 weeks old.

To analyze the morphology of individual neurons in brain slices from MitoPark mice during the early stages of disease, researchers used a technique called whole-cell patch clamp — a technique that allows the study of the electrical properties of neurons — together with fluorescent labeling.

At 16 weeks of age, these animals’ dopaminergic neurons were significantly reduced in size with a lower number of branching points in dendrites — the long, slender projections of a neuron that carry an electrical signal from the cell body to the point of contact with another neuron, called the synapse.

“Alterations in somatic [cell body] and dendritic structure are likely to have direct effects on dopamine-dependent motor function and reward learning. In these neurons, dendrites serve important roles as sites for synaptic termination and contribute to many determinants of cell excitability,” the researchers said.

These defects worsened significantly as animals got older, from 16 to 31 weeks of age, eventually leading to neuronal death.

“Dendritic branching and soma size, although intact in dopamine neurons from 12-week-old MitoPark mice, are progressively and severely disrupted in a manner that undoubtedly impairs cellular function in advance of neuronal death,” the researchers wrote.

Although this decline in neuron morphology occurred at a similar rate in animals from both sexes, it did not begin until after the age at which the first mild locomotor and learning alterations start to occur (approximately 12 weeks).

As a result, the progressive and severe decline in neuronal morphology that occurs prior to cell death does not seem to be involved in the initial motor and cognitive impairments observed in this mouse model.

“This work could help identify the ideal time window for specific treatments to halt disease progression and avert debilitating motor deficits in Parkinson’s patients,” the researchers concluded.

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Inhibiting USP13 Enzyme Can Help Destroy Toxic Alpha-Synuclein Clumps, Mouse Study Finds

USP13 parkin alpha-synuclein

Inhibiting an enzyme called USP13 may represent an attractive therapeutic target for Parkinson’s and other neurodegenerative diseases, preclinical data suggests.

These findings also could hold important implications for a therapy currently being developed to treat Parkinson’s disease — nilotinib.

The study, “Ubiquitin specific protease-13 independently regulates parkin ubiquitination and alpha-synuclein clearance in alpha-synucleinopathies,” was published in Human Molecular Genetics.

USP13 belongs to a large family of enzymes called de-ubiquitinases known for their ability to cut chains of a small protein known as ubiquitin that is present inside stress-induced clumps of proteins and other molecules.

Ubiquitination is like a cellular tagging system: By adding an ubiquitin molecule to a protein, it marks it for degradation.

Previous research has shown that USP13 and another similar enzyme called USP5 are important in helping to dismantle clumps of molecules that form when cells are stressed by external factors, called “stress granules.”

Now Georgetown University Medical Center researchers have found that one reason clumps of alpha-synuclein, known as Lewy bodies, develop and accumulate in the brain is that USP13 removes all the “tags” placed on alpha-synuclein that mark it for destruction, or ubiquitination. Toxic aggregates of alpha-synuclein accumulate and are not efficiently cleared.

Researchers analyzed brain tissue samples collected postmortem from 11 patients with Parkinson’s disease. USP13 levels were about 3.5 times higher than samples from subjects not affected by Parkinson’s.

To better understand the role of USP13, researchers used a genetic approach to either increase or decrease the levels of USP13 in mouse neurons cultured in a laboratory dish. These neurons expressed high levels of alpha-synuclein.

The presence of alpha-synuclein alone significantly increased the levels of parkin ubiquitination. Parkin is a protein often found mutated in some Parkinson’s patients.

The team had previously shown that an increase in parkin ubiquitination led to clearance of neurotoxic proteins, including alpha-synuclein, in several animal models of neurodegeneration.

However, expression of high levels of USP13 and alpha-synuclein together significantly reduced parkin ubiquitination, suggesting that USP13 can modulate parkin response.

“Taken together, these data suggest that USP13 may regulate parkin ubiquitination/de-ubiquination cycle,” the researchers wrote.

Additional experiments revealed that decreasing the levels of USP13 increased alpha-synuclein ubiquitination and destruction.

Knocking out the USP13 gene in a mouse model of Parkinson’s disease was able to prevent alpha-synuclein-induced death of dopamine-producing brain cells. Also, genetic inhibition of USP13 led to significant improvement in animals’ motor performance, while improving the clearance of alpa-synuclein toxic molecules.

Importantly, researchers found that a new therapy being studied to treat Parkinson’s disease, nilotinib, worked better when USP13 was inhibited.

Results from a recent Phase 2 clinical trial (NCT02954978) conducted by Novartis showed that nilotinib can modulate dopamine levels and metabolism, as well as prevent the formation of toxic alpha-synuclein aggregates.

Nilotinib is available under the brand name Tasigna as an approved treatment for certain types of leukemia.

“Our discovery clearly indicates that inhibition of USP13 is a strategic step to activate parkin … to increase toxic protein clearance,” Charbel Moussa, PhD, director of Georgetown University Medical Center Translational Neurotherapeutics Program and senior author of the study, said in a press release. “Our next step is to develop a small molecule inhibitor of USP13 to be used in combination with nilotinib in order to maximize protein clearance in Parkinson’s and other neurodegenerative diseases.”

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IL-4 Cytokine, an Anti-Inflammatory Molecule, Linked to Neuron Damage in Early Parkinson’s Study

interleukin-4, Parkinson's

The anti-inflammatory molecule interleukin (IL)-4 contributes to the neurodegeneration observed in Parkinson’s disease, a study in rats reports.

The research, “Interleukin-4 Contributes to Degeneration of Dopamine Neurons in the Lipopolysaccharide-treated Substantia Nigra in vivo,” was published in the journal Experimental Neurobiology.

Parkinson’s is characterized by the progressive loss of dopamine-producing neurons in the substantia nigra a midbrain area key to muscle control — resulting in lower levels of dopamine, a neurotransmitter, and Parkinson’s motor symptoms.

Brain inflammation is increasingly associated with Parkinson’s progression. Both post-mortem samples of human brains and animal disease models show reactive microglia – nerve cells involved in immune responses to infection or injury. Microglia release pro-inflammatory molecules called cytokines, which are involved in neurodegeneration in the substantia nigra. However, the precise mechanism linking microglia to neuronal loss remains unclear.

IL-4 is a cytokine of benefit to patients with sepsis or multiple sclerosis, and also is involved in brain repair after stroke (cytokines are small proteins of importance to cell communication or signaling). In a mouse model of Alzheimer’s, IL-4 delivered through gene therapy was seen to increase neurogenesis — the formation of neurons from neural stem cells — and learning.

But its role in neurodegeneration has been controversial. On one hand, IL-4 has been linked to the death of reactive (damaging) microglia and to neuronal survival. On the other, microglia expressing IL-4 were shown to promote neurodegeneration in rats administered with amyloid-beta – the major component of senile plaques – or thrombin, an enzyme involved in blood coagulation.

To better understand IL-4’s possibly damaging role in Parkinson’s disease, researchers in Korea analyzed dopamine-producing neurons in rats injected in the substantia nigra with an inflammatory activator called lipopolysaccharide (LPS).

Compared to a control group of rats, those given LPS had a significant loss (62%) of dopamine-producing neurons in the substantia nigra at three and seven days post-injection. LPS-injected brains revealed activated microglia and degenerated dopaminergic neurons. Higher levels of phagocytes (cells that provide innate immunity) were also found in LPS-injected animals.

Data showed higher IL-4 levels  in the substantia nigra of LPS-injected rats as early as one day after injection, reaching a peak at day three. IL-4 was found exclusively in activated microglia.

Injecting an IL-4 neutralizing antibody to inhibit IL-4 significantly eased LPS-induced toxicity, as shown by greater numbers of neurons in the substantia nigra, including those that produce dopamine.

The neutralizing antibody also blocked microglia activation and production of IL-1beta, a cytokine involved in inflammation. Levels of IL-1beta are known to be higher than usual in the cerebrospinal fluid (the liquid filling the brain and spinal cord) of Parkinson’s patients.

Researchers also observed that neutralizing IL-4 rescued LPS-caused disruption of the blood brain barrier (BBB) — a semipermeable membrane that protects the brain — and which showed evidence of “leakage” in LPS rats compared to controls. Damage to the BBB is observed in Parkinson’s patients.

The antibody was also able to halt the depletion of substantia nigra-specific astrocytes — a cell linked to BBB maintenance and formation — at three days post-injection.

“In the present study, IL-4 contributes to microglial activation, production of IL-1β, and disruption of BBB and astrocytes which subsequently led to the degeneration of [dopamine] neurons in the LPS-treated [susbtantia nigra],” the researchers wrote.

“Our results suggest that IL-4 could play the detrimental roles in neurodegenerative diseases such as [Parkinson’s].”

The post IL-4 Cytokine, an Anti-Inflammatory Molecule, Linked to Neuron Damage in Early Parkinson’s Study appeared first on Parkinson’s News Today.

Source: Parkinson's News Today