News ArchivesRead News

Parkinson's protein causes disease spread in animal model, suggesting way disorder progresses over time in humans

Wednesday April 18, 2012

Penn researchers have shown that brain tissue from a Parkinson's disease mouse model , as well as synthetically produced disease protein fibrils, injected into young, symptom-free PD mice led to spreading of PD pathology.

Medical Press - Last year, researchers from the Perelman School of Medicine at the University of Pennsylvania found that small amounts of a misfolded brain protein can be taken up by healthy neurons, replicating within them to cause neurodegeneration. The protein, alpha-synuclein (a-syn), is commonly found in the brain, but forms characteristic clumps called Lewy bodies, in neurons of patients with Parkinson's disease (PD) and other neurodegenerative disorders. They found that abnormal forms of a-syn called fibrils acted as "seeds" that induced normal a-syn to misfold and form aggregates.

In earlier studies at other institutions, when fetal nerve cells were transplanted into the brains of PD patients, some of the transplanted cells developed Lewy bodies. This suggested that the corrupted form of a-syn could somehow be transmitted from diseased neurons to healthy ones.

Now, in a follow-up study published in the Journal of Experimental Medicine, the team, led by senior author Virginia M.-Y Lee, PhD, director of the Center for Neurodegenerative Disease Research and professor of Pathology and Laboratory Medicine, showed that brain tissue from a PD mouse model , as well as synthetically produced a-syn fibrils, injected into young, symptom-free PD mice led to spreading of a-syn pathology. By three months after a single injection, neurons containing abnormal a-syn clumps were detected throughout the mouse brains. The inoculated mice died between 100 to 125 days post-inoculation, out of their typical two-year life span.

"We think the spreading is via white-matter tracks through brain neural network connections," explains Lee. "This study will open new opportunities for novel Parkinson's disease therapies."

"It's like a biochemical chain reaction," says first author Kelvin C. Luk, Ph.D., research associate, in the CNDR. Once inside the confines of a neuron, the misfolded a-syn recruits normally shaped a-syn protein that is present in the cell, causing them to eventually misfold. This occurs along the axons and dendrites (neuronal extensions that reach other neurons), leading to a dramatic accumulation of the abnormal protein. The misshapen a-syn then invades other neurons when they reach the synapse, the small space between neurons.

This transmission process is remarkably similar to what is seen in prions, the protein agents responsible for conditions such as transmissible spongiform encephalopathies ( mad cow disease). However, the researchers are quick to caution that there is no evidence that Parkinson's or any related neurodegenerative diseases is either infectious or acquired.

The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases, but the factors that trigger aggregation of a-syn are poorly understood.

The Penn team saw that misfolded a-syn propagated along major central nervous system pathways, reaching regions far beyond injection sites. What's more, they showed for the first time that synthetically produced a-syn fibrils are sufficient to initiate a vicious cycle of Lewy body formation and transmission of the misfolded a-syn in mice.

The study demonstrates just how the Parkinson's disease protein can spread in a patient's brain in terms of uptake into a healthy neuron, expansion within the cell, and finally release to a neighboring neuron.

"Knowing this mechanism allows for possible immunotherapies to interrupt the chain reaction by stopping the mutant protein from spreading at the synapse," says Lee.

"Shedding light on how α-synuclein contributes to Parkinson's disease and related Lewy body disorders is of significant interest both for understanding these diseases and developing potential treatments," said Beth-Anne Sieber, Ph.D., of the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health. "This study provides evidence for the progressive, pathological spread of α-synuclein through the brain."

Provided by University of Pennsylvania School of Medicine (news : web)


Recent News

Nov 22 - A caregiver's story: Living and loving through the slow process of dying
Nov 19 - Testosterone cause of sex differences in the occurrence of Parkinson’s disease, new research suggests
Nov 18 - New strategy reduces side effects in Parkinson's treatment
Nov 14 - Opinion: The never-ending tests of Parkinson's disease
Nov 13 - Parkinson’s disease: A new tool for diagnosis
Nov 10 - Parkinson's Disease Drug May Be Useful For Delaying, Preventing Blindness In Older Population
Nov 9 - Microsoft VP’s diagnosis fuels employees’ heartfelt efforts to help others
Nov 6 - Lewy body dementia: unrecognized and misdiagnosed
Nov 5 - Gait difficulties in Parkinson's linked to new blood vessels in brain
Oct 30 - Special Section: Enabling Technologies for Parkinson’s Disease Management
Oct 27 - Scientists discover a 'switchboard' of molecules that protect against Parkinson's disease
Oct 26 - Dancing improves mobility and quality of life in people with Parkinson's
Oct 23 - The amazing woman who can smell Parkinson’s disease — before symptoms appear
Oct 20 - Personal Essay: The deviousness of dementia
Oct 19 - Mechanism that 'melts' protein clumps may lead to new Parkinson's treatments
Oct 19 - Researchers find that stem cell treatment may reduce cognitive impairment related to dementia with Lewy bodies
Oct 17 - Cancer Drug Helps Parkinson's Patients
Oct 12 - Researchers identify immune gene that can prevent Parkinson's disease and dementia
Oct 12 - Blog Post: An Alert, Well-Hydrated Artist in No Acute Distress
Oct 7 - This month, a brain surgery will be broadcast on live TV for the first time ever