Genetic disease offers insights for Parkinson’s treatment
Protein clumps in GAN hamper brain function, mouse study finds
A rare nerve disorder may offer clues to potential Parkinson’s disease treatment targets, a mouse study showed.
In giant axonal neuropathy (GAN), buildup of neurofilament proteins trap several cellular organelles and proteins, preventing nerve cells from clearing and recycling waste, the study found. Because neurofilament proteins have also been linked to several neurodegenerative disorders, the findings may be relevant to Parkinson’s, the researchers said.
The study, “Neurofilament accumulation disrupts autophagy in giant axonal neuropathy,” was led by researchers at Northwestern University in Chicago, in collaboration with the University of North Carolina at Chapel Hill. It was published in JCI Insight.
GAN is a rare genetic disease that starts in childhood and is caused by mutations in the GAN gene, which provides instructions for producing a protein called gigaxonin. This protein helps break down neurofilaments, and when it’s faulty or missing, neurofilaments accumulate and damage nerve cells.
Neurofilaments form the framework that shapes nerve cell extensions called axons, which are key for sending signals in the nervous system. When nerve cells are damaged, they release neurofilaments into the fluid around the brain and spinal cord. They then flow into the bloodstream, where they can be easily measured.
Target for Parkinson’s treatment
High levels of a type of neurofilament called neurofilament light chain is linked to early signs of Parkinson’s, such as problems with sleep, and faster progression of symptoms. Studies have shown that levels of this neurofilament type can also predict cognitive decline and mortality in late-stage Parkinson’s.
“The accumulation of these proteins … can be used as a biomarker for the progression of a variety of neurological diseases, from peripheral neuropathies to multiple sclerosis, amyotrophic lateral sclerosis, dementias, and [Parkinson’s] and [Alzheimer’s],” the researchers wrote.
To understand how neurofilaments contribute to neurodegeneration, the researchers turned to a mouse model of GAN. That’s because unlike other neurodegenerative diseases, GAN arises from problems with neurofilaments themselves.
“When you have these other diseases, when so much else is going on, it’s difficult to pinpoint the role of neurofilaments,” Puneet Opal, MD, PHD, the study’s senior author and a neurology professor at Northwestern University, said in a university news story. “But here, with this genetic disease, we basically honed in on this very singular pathway.”
The researchers “wanted to understand whether there could be an alternative pathway for degrading proteins which could be upregulated [turned on] when the gigaxonin pathway is mutated,” said Opal, who also directs the Denning Ataxia Center at Northwestern’s Feinberg School of Medicine.
Compared with nerve cells of healthy mice, those of mice lacking the GAN gene had impaired autophagy, the cellular process by which sac-like structures called vesicles pack waste, carrying it to lysosomes, where enzymes break it down for recycling.
This impairment happened in two ways. First, the buildup of neurofilaments blocked the movement of autophagic vesicles within nerve cells, preventing them from breaking down waste. Second, neurofilaments trapped a protein called 14-3-3, which helps control another key protein, TFEB, that regulates autophagy.
“These vesicles can’t reach the garbage can — lysosomes,” Opal said. “So, the neurofilaments cannot be degraded by that. Additionally, the neurofilaments create docking sites for proteins and organelles normally, but in the disease, these sites are a little bit garbled.”
In Parkinson’s, problems with lysosomes can cause misfolded alpha-synuclein proteins to build as toxic clumps. These clumps cause the death of nerve cells that produce dopamine, a chemical that signals for motor control. Loss of dopamine results in the hallmark Parkinson’s motor symptoms.
“Future studies will be required to tease out the complex interactions between signaling pathways, organelle dysfunction, and [neurofilament] aggregation to determine strategies to best treat GAN,” the researchers wrote.
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