Summary: Alpha synuclein’s non-amyloidal component (NAC) aids the protein’s movement through axons. When the NAC region is removed, alpha-synuclein did not move within axons.
Source: University at Buffalo
Research by University at Buffalo biologists is providing new insights into alpha-synuclein, a small acidic protein associated with Parkinson’s disease.
Alpha-synuclein is known to form abnormal clumps in the brains of patients with Parkinson’s, but scientists are still trying to understand how and why this happens.
The new study explores alpha-synuclein’s basic properties, with a focus on a section of the protein known as the non-amyloidal component (NAC). The research was done on fruit fly larvae that were genetically engineered to produce both normal and mutated forms of human alpha-synuclein.
The study, led by University at Buffalo biologist Shermali Gunawardena, was published on Jan. 10 in the journal Frontiers in Cellular Neuroscience.
Some key findings:
The NAC region appears to aid alpha-synuclein in moving through pathways called axons that run from one area of a neuron to another. When the NAC region was missing, alpha-synuclein did not move within axons.
Alpha-synuclein that’s missing the NAC region may help to prevent unwanted aggregates of the protein. In experiments, Gunawardena’s team showed that it’s possible — at least in fruit flies — to prevent some key problems that occur when too much alpha-synuclein is produced: clumping of the protein; abnormalities in the structure of synapses, which form connections between neurons; and a decrease in the speed at which larvae crawl. The scientists found that when the larvae are engineered to produce both excess alpha-synuclein and a version of alpha-synuclein with the NAC region missing, the larvae crawl normally, the protein doesn’t aggregate, and the synapses are normal.
“We show that in fruit fly larvae, we’re able to prevent some problems mimicking symptoms of Parkinson’s disease, such as accumulation of alpha-synuclein in neurons,” says Gunawardena, PhD, associate professor of biological sciences in the UB College of Arts and Sciences.
“Our work highlights a potential early treatment strategy for Parkinson’s disease that would leverage the use of deletion of the NAC region,” Gunawardena adds. “One reason this study is important is because it shows rescue of alpha-synuclein aggregates, synaptic morphological defects and locomotion defects seen in Parkinson’s disease in the context of a whole organism.”
The paper’s first author is Eric N. Anderson, a UB PhD graduate in biological sciences. In addition to Anderson and Gunawardena, co-authors include UB undergraduate students Delnessaw Hirpa and Kan Hong Zheng, who have since completed their degrees, as well as Rupkatha Banerjee, a current UB PhD candidate in biological sciences.
Funding: The research was partially funded by the National Institute of Neurological Disorders and Stroke in the National Institutes of Health, and the John R. Oishei Foundation. Anderson was supported by the Arthur A. Schomburg Fellowship Program at UB.
About this neuroscience research article
Source: University at Buffalo Media Contacts: Charlotte Hsu – University at Buffalo Image Source: The image is credited to Anderson, Hirpa, Zheng, Banerjee and Gunawardena, Frontiers in Cellular Neuroscience,.
The Non-amyloidal Component Region of α-Synuclein Is Important for α-Synuclein Transport Within Axons
Proper transport of the Parkinson’s disease (PD) protein, α-synuclein (α-syn), is thought to be crucial for its localization and function at the synapse. Previous work has shown that defects in long distance transport within narrow caliber axons occur early in PD, but how such defects contribute to PD is unknown. Here we test the hypothesis that the NAC region is involved in facilitating proper transport of α-syn within axons via its association with membranes. Excess α-syn or fPD mutant α-synA53T accumulates within larval axons perturbing the transport of synaptic proteins. These α-syn expressing larvae also show synaptic morphological and larval locomotion defects, which correlate with the extent of α-syn-mediated axonal accumulations. Strikingly, deletion of the NAC region (α-synΔ71–82) prevented α-syn accumulations and axonal blockages, and reduced its synaptic localization due to decreased axonal entry and axonal transport of α-syn, due to less α-syn bound to membranes. Intriguingly, co-expression α-synΔ71–82 with full-length α-syn rescued α-syn accumulations and synaptic morphological defects, and decreased the ratio of the insoluble higher molecular weight (HMW)/soluble low molecular weight (LMW) α-syn, indicating that this region is perhaps important for the dimerization of α-syn on membranes. Together, our observations suggest that under physiological conditions, α-syn associates with membranes via the NAC region, and that too much α-syn perturbs axonal transport via aggregate formation, instigating synaptic and behavioral defects seen in PD.