Yearly Archives: 2017

The development of Parkinson's disease is linked to an overabundance of the protein alpha-synuclein, which is found mainly at the end of neurons in what is called the nerve terminal. Since the link was first discovered in the 1990s, researchers have been working to precisely identify its role in Parkinson’s disease.

Now scientists have found that alpha-synuclein hinders a key step involved in the transmission of neuronal signals, which is essential for higher-brain functioning: vesicle endocytosis at the nerve terminal.

The study was published in the Journal of Neuroscience.

Neurotransmission is a process that allows neurons to pass signals between one another — signals important for motor, sensory, and cognitive functioning. When an electrical signal arrives at a nerve terminal and needs to be passed along to the next neuron, neurotransmitters packed in vesicles mediate this process. After being released, the neurotransmitter is caught by receptors in an adjacent neuron and the signal is passed along for further transmission. Meanwhile, the empty vesicle is recycled back into the nerve terminal to be used again.

The retrieval of an emptied vesicle membrane is called "endocytosis," and it is this process that an overabundance of alpha-synuclein disrupts. Endocytosis is critical for proper neurotransmission — when it is inhibited, the rest of the steps involved in transmission are affected as well.

High-frequency transmission, in which vesicles are heavily used, is important for processes such as sensory perception, generating memories, and motor control. The researchers found that when endocytosis is inhibited, high-frequency transmission breaks down much more quickly than it would under normal circumstances.

A deeper look into the mechanism by which alpha-synuclein inhibits endocytosis revealed toxic effects of the over-assembly of microtubules. Too much alpha-synuclein in the nerve terminal causes microtubules to over-assemble and somehow get in the way of endocytosis.

Researchers believe that this inhibitory process caused by an overabundance of alpha-synuclein is what occurs in the early stages of Parkinson's disease, before morphological changes such as the loss of function and death of neurons begins.

Paper: “Wild-type monomeric α-synuclein can impair vesicle endocytosis and synaptic fidelity via tubulin polymerization at the calyx of Held”
Reprinted from materials provided by Okinawa Institute of Science and Technology Graduate University – OIST.

A phase 2 clinical trial in young adults with Down syndrome of a drug being investigated for the treatment of Alzheimer’s disease supports further investigation of its potential, according to the researchers behind the four-week trial of scyllo-inositol, also known as ELND005. The results have been published in the Journal of Alzheimer’s Disease.

The most common form of intellectual disability in the United States, Down syndrome is caused by an extra copy of chromosome 21. People with Down syndrome exhibit various degrees of intellectual disability and are at greatly increased risk of developing Alzheimer's dementia as they age. Excess activity of the genes on chromosome 21 — including the gene for the amyloid precursor protein, the source of amyloid plaques found in the brains of people with Alzheimer's disease — is thought to play a role in the cognitive challenges of people with Down syndrome.

Another chromosome 21 gene believed to play a role in Down syndrome contributes to the metabolism of myo-inositol, a signaling molecule increased in the brains of children and adults with Down syndrome at levels that correlate to the severity of symptoms. Lifelong exposure to increased levels of both amyloid and myo-inositol are believed to contribute to brain dysfunction and cognitive disability. Scyllo-inositol may have potential to improve cognition in patients with Down syndrome both by decreasing amyloid levels and regulating myo-inositol-dependent signaling in the brain.

The clinical trial enrolled 23 adults with Down syndrome, ages 18 to 45, who were randomised to receive one of two dosages of scyllo-inositol — 250 mg either daily or twice a day — or a placebo. All but one participant completed the four-week trial with no significant deviations from the protocol. There were no serious adverse events and no changes in vital signs, laboratory tests or other physical findings. While treatment produced no apparent cognitive or behavioral changes, the duration of the trial was too short to capture such effects.

A multi-institutional team of researchers has discovered how a potential treatment strategy for Huntington’s disease (HD) produces its effects, verified its action in human cells and identified a previously unknown deficit in neural stem cells from patients with HD.

In their report, published in Proceedings of the National Academy of Sciences, the team describes finding how a group of compounds activates the NRF2 molecular pathway, which protects cells from several damaging influences, and also discovering that NRF2-mediated activity appears to be impaired in neural stem cells from the brains of HD patients.

A 2016 study by the same researchers identified a compound, which the investigators named MIND4, that appeared to protect against HD-associated neurodegeneration in two ways — by activating the NRF2-mediated pathway and by inhibiting the regulatory enzyme SIRT2, a strategy also being investigated to treat Parkinson's disease. A related compound, called MIND4-17, was found to only activate the NRF2 pathway but to do so more powerfully than did MIND4. The current investigation's overall goal was to examine whether the NRF2 activation responses observed in that study were also present in human cells, indicating their potential for therapeutic development.

The investigators found that MIND4-17 acts by mimicking the same process that activates the NRF2 pathway in response to oxidative stress. In stress-free conditions NRF2 is bound into a complex by two other proteins, one of which mediates a process leading to the breakdown of NRF2. MIND4-17 binds to and modifies the mediating protein in way that changes the shape and arrests formation of the protein complex, thereby allowing newly synthesized NRF2 to escape degradation and move to the nucleus where it can activate protective antioxidant genes.

NRF2 activation also induced anti-inflammatory effects in microglia and macrophages, immune cells known to infiltrate the brain in late-stage HD; and treatment with MIND4, which crosses the blood-brain barrier, reduced levels of a key inflammatory protein in a mouse model of HD.

In human neural stem cells from patients with HD — cells reflecting a range of the CAG nucleotide repeats found in the mutated gene that underlies the disorder — NRF2 activation in response to MIND4-17 was found to be reduced at levels correlating with the number of repeats.

Since MIND4-17 is unable to penetrate the blood brain barrier, future work is needed to develop powerful NRF2-activating compounds with enhanced brain permeability and to test their efficacy in models of HD and other neurodegenerative disorders.

Paper: “KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients”

Reprinted from materials provided by Massachusetts General Hospital

For people with dementia, communicating needs, emotions and interacting with others becomes increasingly difficult as communication deteriorates as dementia progresses. Problems in communicating lead to misinterpretations and misunderstandings, which often cause considerable stress for family members, especially the spouse caregivers, as well as the patients.

But all is not lost according to the first study to look at and measure communication outcomes in both the caregiver spouse and the patient with dementia. In fact, researchers have found that “practice makes perfect” with the right intervention and a tool that can accurately measure couples’ communication. Results from the study are published in the journal Issues in Mental Health Nursing.

For the study, the researchers videotaped and later analyzed and measured 118 conversations between 15 patients with varying degrees of dementia and their spouses — married an average of 45 years — to evaluate the effects of a 10-week communication-enhancement intervention on participants’ communication and mental health.

Caregivers were taught to communicate in a manner that was clear, succinct and respectful, and to avoid testing memory and arguing. Spouses with dementia were given the opportunity to practice their conversation skills with a member of the research team who was trained in communication deficits associated with dementia as well as the intervention. Conversations were recorded at the couples’ homes. After setting up the video camera, the researchers conducted the intervention and then left the room for 10 minutes. Couples were instructed to converse on a topic of their choice for 10 minutes.

Unlike other measures of patient communication, the Verbal and Nonverbal Interaction Scale-CR (VNIS-CR) tool takes into account nonverbal behaviors, which account for more than 70 percent of communication, as well as verbal behaviors. VNIS-CR delineates social and unsociable behaviors, characterizes patient behaviors (not through the lens of a caregiver), and is targeted to spousal relationships in the home. Consisting of 13 social and 13 unsociable communication behaviors with both verbal and nonverbal items, the tool helps to describe sociable and unsociable communication in patients with dementia as they engage in conversations with their spouses.

The VNIS-CR could be used in clinical practice to describe changes in social communication abilities over time, as well as to educate spousal caregivers about the importance of encouraging sociable communication. Knowledge gained from using this tool could better guide the development of interventions to support intimate relationships and ultimately measure changes following those interventions.

Paper: “Preliminary Psychometric Properties of the Verbal and Nonverbal Interaction Scale: An Observational Measure for Communication in Persons with Dementia”
Reprinted from materials provided by Florida Atlantic University.