Nobody really knows, and that’s a problem in addressing diseases that affect the brain, says Marvin Bentley, an assistant professor of biological sciences at Rensselaer Polytechnic Institute and member of the Center for Biotechnology and Interdisciplinary Studies. Trafficking errors show up in most neurodegenerative diseases — including Parkinson’s, Alzheimer’s, and Huntington’s — and yet so little is known about the how cells build, move, and deliver transmembrane proteins that researchers don’t know whether trafficking errors cause or are caused by these diseases.

“This is a fundamental aspect of how the brain works and no one really understands it,” said Bentley, an expert in live imaging of transmembrane protein trafficking who joined Rensselaer in 2017. “My goal is to answer basic scientific questions about this process.”

In a lab that combines diverse skills and disciplines — growing neurons, cultivating tissues, employing biochemistry, molecular biology and live imaging — Bentley has developed a series of research techniques that make it possible to view and track packages of transmembrane proteins as motor proteins carry them to their destination.

“Dr. Bentley’s work is making it possible to track proteins moving through a living neuron in real time, a crucial component in the study of this basic neurological function,” said Curt Breneman, dean of the Rensselaer School of Science. “The information, and the insights derived from the live images he is producing, will advance the field of neuroscience and aid us in tackling crippling disorders. We are very pleased to welcome him as a colleague.”

With their stark division, nerve cells face a specific challenge in this process, which is known as selective vesicle transport. But all cells must accurately route various transmembrane proteins, which — when delivered — span the membrane of living cells and organelles, connecting the interior with exterior, and moving resources and waste from one side to the other. Throughout the life of the cell, transmembrane proteins are replaced as they wear out, creating a constant traffic of proteins being moved from the cellular factories where they are formed to their destination.

Transmembrane proteins are first assembled in the membrane of an organelle called the endoplasmic reticulum. When the proteins are assembled, a patch of membrane containing at least one transmembrane protein buds from the wall of the organelle and forms a spherical package called a vesicle. The vesicle binds to a “tail” at one end of a motor protein. The other end of the motor protein, the “motor domain,” has two “feet” that use chemical energy to walk along molecular highways crisscrossing the cell, ferrying the transmembrane protein to its destination.

Regulation of this journey takes many forms, and in one aspect of his current research, Bentley is examining the relationship between the vesicles and the motor proteins that carry them. This relationship is riddled with unknowns: Nerve cells create an unknown number of axon- or dendrite-specific transmembrane proteins, which can be packaged in an unknown number of vesicles, and are ferried by up to 20 different motor proteins in a class called kinesins.

To better examine these relationships, Bentley has pioneered a series of techniques — including several variations of modified and fluorescently tagged motor proteins — that allow him to visualize motor proteins while they’re moving vesicles in cells. His techniques make is possible for him to see which vesicles specific motor proteins are moving and where they travel, and to manipulate motor proteins and observe how that affects movement.

“Our goal is to figure out the very basics of how the cell works, how neurons work, and hopefully in the future it will be possible to correlate that back to these diseases and devise treatments,” said Bentley. His research is supported by National Institutes of Health R01 grant MH066179 “Neuronal Polarity and Membrane Trafficking.”

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Materials provided by Rensselaer Polytechnic Institute (RPI). Original written by Mary L. Martialay. Note: Content may be edited for style and length.

This study looked specifically at the effect of alcohol use disorders, and included people who had been diagnosed with mental and behavioural disorders or chronic diseases that were attributable to chronic harmful use of alcohol.

Of the 57,000 cases of early-onset dementia (before the age of 65), the majority (57%) were related to chronic heavy drinking.

The World Health Organization (WHO) defines chronic heavy drinking as consuming more than 60 grams pure alcohol on average per day for men (4-5 Canadian standard drinks) and 40 grams (about 3 standard drinks) per day for women.

As a result of the strong association found in this study, the authors suggest that screening, brief interventions for heavy drinking, and treatment for alcohol use disorders should be implemented to reduce the alcohol-attributable burden of dementia.

“The findings indicate that heavy drinking and alcohol use disorders are the most important risk factors for dementia, and especially important for those types of dementia which start before age 65, and which lead to premature deaths,” says study co-author and Director of the CAMH Institute for Mental Health Policy Research Dr. Jürgen Rehm. “Alcohol-induced brain damage and dementia are preventable, and known-effective preventive and policy measures can make a dent into premature dementia deaths.”

Dr. Rehm points out that on average, alcohol use disorders shorten life expectancy by more than 20 years, and dementia is one of the leading causes of death for these people.

For early-onset dementia, there was a significant gender split. While the overall majority of dementia patients were women, almost two-thirds of all early-onset dementia patients (64.9%) were men.

Alcohol use disorders were also associated with all other independent risk factors for dementia onset, such as tobacco smoking, high blood pressure, diabetes, lower education, depression, and hearing loss, among modifiable risk factors. It suggests that alcohol use disorders may contribute in many ways to the risk of dementia.

“As a geriatric psychiatrist, I frequently see the effects of alcohol use disorder on dementia, when unfortunately alcohol treatment interventions may be too late to improve cognition,” says CAMH Vice-President of Research Dr. Bruce Pollock. “Screening for and reduction of problem drinking, and treatment for alcohol use disorders need to start much earlier in primary care.” The authors also noted that only the most severe cases of alcohol use disorder — ones involving hospitalization — were included in the study. This could mean that, because of ongoing stigma regarding the reporting of alcohol-use disorders, the association between chronic heavy drinking and dementia may be even stronger.

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“This report is an important contribution in our efforts to understand and quantify Parkinson’s biology to accelerate drug development,” said Mark Frasier, PhD, an author on the study and the senior vice president of research programs at the Michael J. Fox Foundation, which provided funding for the study.

A mysteriously harmful presence

Alpha-synuclein’s function in the brain is currently unknown but of great interest to Parkinson’s researchers because it is a major constituent of Lewy bodies — the protein clumps that are the pathological hallmark of Parkinson’s disease.

The illness gradually destroys neurons that produce the chemical dopamine, which conveys nerve signals, in turn causing the tremors and difficulty moving that are a common symptom of Parkinson’s disease. The prevailing wisdom has been that these neurons may die from a toxic reaction to alpha-synuclein deposits.

However, Parkinson’s disease has been linked to some gene variants that affect how the immune system works, leading to an alternative theory that alpha-synuclein causes Parkinson’s disease by triggering the immune system to attack the brain.

In addition to its presence in the brain, alpha-synuclein can be found in peripheral tissues and body fluids. The Movement Disorders study, called BioFIND, is the first to try to differentiate the biomarkers of neurodegeneration in Parkinson’s disease patients based on fluids collected from spinal fluid, blood and saliva.

The cross-sectional, observational study collected data and body fluid samples from 120 people with moderately advanced Parkinson’s disease and 100 control volunteers across eight academic sites in the U.S. at two points over two weeks.

Dr. Jennifer G. Goldman, a movement disorders neurologist at Rush University Medical Center and the study lead author, has profiled the Parkinson’s-associated protein levels in these biofluids and their relationships to clinical features of the disease. The study found that levels of alpha-synuclein were lower in cerebrospinal fluid from Parkinson’s patients with certain motor function impairments — specifically in those who had more problems with balance and walking compared to those with more tremor.

In addition, levels of beta-amyloid, known for its association with Alzheimer’s disease, were lower in those with Parkinson’s and related to worse scores on a memory recall in Parkinson’s as measured on a rest of thinking and memory given to study participants.

The study also showed that alpha-synuclein levels in plasma and saliva did not differ between people with Parkinson’s and control volunteers, and alpha-synuclein did not significantly correlate among other biological fluids.

Findings can help guide selection for clinical trials

“These are important insights for the ongoing pursuit of accessible biomarker tests to diagnose and track the disease,” said Goldman. “For example, people with Parkinson’s and lower beta-amyloid may be more likely to develop memory problems and therefore would benefit more from a cognitive therapy,” said Goldman. “Enrolling this population in trials can help us see a treatment effect more clearly than testing the therapy on people who will not have this symptom.”

Future studies may further explore biomarkers

Next steps include validation of these findings in the Parkinson’s Progression Markers Initiative (PPMI), a biomarkers study sponsored by the Michael J. Fox Foundation that is following more than 1,500 people with Parkinson’s or risk factors and control volunteers over at least five years. Additionally, trials ongoing or launching in the near future could use alpha-synuclein or beta-amyloid levels as exploratory biomarkers in motor symptom or cognition drug trials, respectively.

Parkinson’s disease is the second most common age-related neurodegenerative disorder after Alzheimer’s disease, affecting an estimated 7 million to 10 million people worldwide.

Many of the affected neurons signal via the neurotransmitter dopamine; therefore, traditional therapy continues to rely on dopamine replacement therapy. This approach alleviates symptoms, but does not halt disease progression. Currently, there is no cure for Parkinson’s disease.

BioFIND is supported in part by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, and led by principal investigator Dr. Un Jung Kang, chief of the Division of Movement Disorders at Columbia University.