Toxic protein aggregates called Lewy bodies sequestrate a protein that is usually found in the cell nucleus and known to protect against neurodegeneration, and change in this protein’s location contributes to the mechanisms underlying Parkinson’s disease, researchers report.
The study, “Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson’s disease patients,” was published in Neuroscience Letters.
Aging is a primary risk factor for Parkinson’s disease as age-related changes in cellular function predispose people to the development of this neurodegenerative disorder.
Evidence suggests a close relationship between neuronal death and toxic protein inclusions, such as Lewy bodies — clumps of alpha-synuclein protein. However, the exact mechanism of how these aggregates result in disease remains to be understood.
“It has been reported that repressor element-1 silencing transcription factor, (also known as) neuron-restrictive silencer factor (REST/NRSF) is induced in the nuclei of aged neurons, preserves neuronal function, and protects against neurodegeneration during aging through the repression of cell death-inducing genes,” the researchers wrote.
Studies have shown that REST expression is decreased in Alzheimer’s disease, but little is known about its role in Parkinson’s disease.
Therefore, researchers from Juntendo University in Japan set to identify the neuroprotective functions of REST in aging and the brains of Parkinson’s disease patients.
The team used post-mortem brain samples of normal aging people (controls), and Parkinson’s or dementia with Lewy bodies patients, and looked at different areas to determine where REST was located within neurons.
In a normal aging (more than 72 years old) brain, REST was present in the nucleus and cytosol (the fluid found inside cells) of dopaminergic neurons present in the substantia nigra — a midbrain area important for muscle control.
This was not the case in the middle-aged brains (age 47 and 61 years), where REST was not observed in the nucleus, and there was a small amount of cytosolic accumulation, suggesting that nuclear entry of REST is dependent on the cellular aging process.
In contrast to healthy controls, REST expression was decreased in patients with Parkinson’s disease and dementia with Lewy bodies, both in the nucleus and cytosol of dopaminergic substantia nigra neurons and cortical neurons. Instead, REST was strongly detected within Lewy bodies.
To dissemble dysfunctional proteins, neurons use two major cellular pathways: the ubiquitin-proteasome system, where short-lived proteins in the cytoplasm and nucleus are degraded by a complex called the proteasome; and the autophagy-lysosome pathway, which digests long-lived proteins and abnormal cellular structures, including mitochondria, the cell’s powerhouse.
The proteasome is a tiny, barrel-shaped cellular structure that degrades toxic non-functional proteins that have been molecularly tagged for destruction.
Disease-related protein aggregates contain ubiquitinated proteins (proteins that have been “tagged” for degradation), and p62 — a molecular receptor that recognizes and shuttles ubiquitinated proteins for degradation.
Researchers wanted to understand whether REST interacted with ubiquitinated protein aggregates. Therefore, they investigated the transcription factor’s location in mouse brain cells that were either normal or were genetically engineered to lack the ability to perform protein degradation (autophagy) specifically in dopaminergic neurons.
In the substantia nigra of normal aging healthy mice (12 months of age), there was no detectable interaction between REST and p62, while in animals with a dysfunctional protein degradation pathway, REST was found in p62-positive aggregates within the cytoplasm. This suggests that REST is incorporated into cytoplasmic aggregates that accumulate as a consequence of autophagy dysfunction.
Therefore, REST aggregating with p62 suggests that it is part of a lesion associated with Lewy body formation.
Scientists then tested if the accumulation of ubiquitinated proteins induced REST gene expression in a human neuroblastoma (a rare type of cancer affecting the nervous system) cell line. Results showed that REST accumulated (was not degraded) in the presence of an autophagy inhibitor called MG132 — which blocks neuronal molecule-degradation systems. However, REST did not accumulate upon the addition of a proteasome-specific inhibitor, called lactacystin, which indicates that REST is dissembled via the autophagy-lysosome pathway.
When researchers added rotenone (a pesticide that inhibits the function of mitochondria) to neurons, REST accumulation increased.
“As rotenone is a possible Parkinson-causing agent, loss of neuronal REST accumulation in aged-neurons may relate to the PD pathology (the typical behaviour of a disease),” the researchers said.
Nuclear accumulation of REST “occurs as a normal aging process and Lewy pathology disturbs the process in dopaminergic neurons by sequestering REST. The alteration of neuronal aging processes including the loss of REST in neurons may associate with the PD pathogenesis,” they concluded.
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