Common RNA Pathway Found in ALS and Dementia
Two proteins previously found to contribute to ALS, also known as Lou Gehrig’s disease, have divergent roles. But a new study, led by researchers at the Department of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine, shows that a common pathway links them.
The discovery reveals a small set of target genes that could be used to measure the health of motor neurons, and provides a useful tool for development of new pharmaceuticals to treat the devastating disorder, which currently has no treatment or cure.
Funded in part by the National Institutes of Health and the California Institute for Regenerative Medicine (CIRM), the study will be published in the advance online edition of Nature Neuroscience on September 30.
ALS is an adult-onset neurodegenerative disorder characterized by premature degeneration of motor neurons, resulting in a progressive, fatal paralysis in patients.
The two proteins that contribute to the disease – FUS/TLS and TDP-43 – bind to ribonucleic acid (RNA), intermediate molecules that translate genetic information from DNA to proteins. In normal cells, both TDP-43 and FUS/TLS are found in the nucleus where they help maintain proper levels of RNA. In the majority of ALS patients, however, these proteins instead accumulate in the cell’s cytoplasm – the liquid that separates the nucleus from the outer membrane, and thus are excluded from the nucleus, which prevents them from performing their normal duties.
Since the proteins are in the wrong location in the cell, they are unable to perform their normal function, according to the study’s lead authors, Kasey R. Hutt, Clotilde Lagier-Tourenne and Magdalini Polymenidou. “In diseased motor neurons where TDP-43 is cleared from the nucleus and forms cytoplasmic aggregates,” the authors wrote, “we saw lower protein levels of three genes regulated by TDP-43 and FUS/TLS. We predicted that this, based on our mouse studies, and found the same results in neurons derived from human embryonic stem cells.”
In 2011, this team of UC San Diego scientists discovered that more than one-third of the genes in the brains of mice are direct targets of TDP-43, affecting the functions of these genes. In the new study, they compared the impact of the FUS/TLS protein to that of TDP-43, hoping to find a large target overlap.
“Surprisingly, instead we saw a relatively small overlap, and the common RNA targets genes contained exceptionally long introns, or non-coding segments. The set is comprised of genes that are important for synapse function,” said principal investigator Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine and the Institute for Genomic Medicine at UC San Diego and a visiting professor at the Molecular Engineering Laboratory in Singapore. “Loss of this common overlapping set of genes is evidence of a common pathway that appears to contribute to motor neuron degeneration.”
In an effort to understand the normal function of these two RNA binding proteins, the scientists knocked down the proteins in brains of mice to mimic nuclear clearance, using antisense oligonucleotide technology developed in collaboration with ISIS Pharmaceuticals. The study resulted in a list of genes that are up or down regulated, and the researchers duplicated the findings in human cells.
“If we can somehow rescue the genes from down regulation, or being decreased by these proteins, it could point to a drug target for ALS to slow or halt degeneration of the motor neurons,” said Yeo.
These proteins also look to be a central component in other neurodegenerative conditions. For example, accumulating abnormal TDP-43 and FUS/TLS in neuronal cytoplasm has been documented in frontotemporal lobar dementia, a neurological disorder that has been shown to be genetically and clinically linked to ALS, and which is the second most frequent cause of dementia after Alzheimer’s disease.
Protein Build-Up Leads to Neurons Misfiring
Imaging technique offers novel way to monitor neurodegenerative disorders in live animal models of Parkinson’s disease
Using a two-photon microscope capable of peering deep within living tissue, researchers at the University of California, San Diego School of Medicine have found new evidence that alpha-synuclein protein build-up inside neurons causes them to not only become “leaky,” but also to misfire due to calcium fluxes.
The findings – the first recorded in vivo using a transgenic mouse model of Parkinson’s disease – are published in the July 18 issue of The Journal of Neuroscience and provide new insights into how Parkinson’s disease and other neurodegenerative disorders known as synucleinopathies work and progress at the cellular level.
Previous in vitro studies using cell cultures had suggested abnormal accumulation of alpha-synuclein dysregulated intracellular handling and movement of calcium, which is used as a signaling molecule and neurotransmitter. It was unclear, however, whether calcium alterations occurred in more complex, living animals.
“This is the first time we’ve been able to verify the role of alpha-synuclein aggregates in vivo,” said senior author Eliezer Masliah, MD, professor of neurosciences and pathology.
“The aggregates affect the cell membrane of neurons, making them more porous. They also affect the membranes of organelles inside neurons, such as the mitochondria that are part of the cell’s machinery for generating energy. Energy is necessary to pump calcium in and out of the cell. If mitochondria membranes are compromised, calcium accumulates, further damaging the neuron and causing it to misfire.”
A human neuron. UC San Diego scientists have identified a pair of proteins that help clear away other misfolded proteins responsible for the progressive degeneration of brain cells in Huntington’s disease.
Two Proteins Offer a “Clearer” Way to Treat Huntington’s Disease
Pair helps remove and prevent misfolding of proteins that cause neurodegeneration
In a paper published in the July 11 online issue of Science Translational Medicine, researchers at the University of California, San Diego School of Medicine have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington’s disease (HD).
The findings explain a fundamental aspect of how HD wreaks havoc within cells and provides “clear, therapeutic opportunities,” said principal investigator Albert R. La Spada, MD, PhD, professor of cellular and molecular medicine, chief of the Division of Genetics in the Department of Pediatrics and associate director of the Institute for Genomic Medicine at UC San Diego.
“We think the implications are significant,” said La Spada. “It’s a lead we can vigorously pursue, not just for Huntington’s disease, but also for similar neurodegenerative conditions like Parkinson’s disease and maybe even Alzheimer’s disease.”
In HD, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central nervous system cells, leading to progressive deterioration of involuntary movement control, cognitive decline and psychological problems. More than 30,000 Americans have HD. There are no effective treatments currently to either cure the disease or slow its progression.
La Spada and colleagues focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function.
“It’s all about energy,” La Spada said. “Neurons have a constant, high demand for it. They’re always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity.”
Previous studies by La Spada and others discovered that the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha. “This study confirms that,” La Spada said. More surprising was the discovery that elevated levels of PGC-1alpha in a mouse model of HD virtually eliminated the problematic misfolded proteins.
