Wang Xin's team from Zhongshan Hospital of Fudan University discovered the key mechanism of neuronal inclusion body disease

Neuronal inclusion body disease (niid) is a degenerative disease that is dominated by the nervous system and can involve muscles, digestive tract, kidneys and other organ systems
.

Widely distributed p62-positive nuclear inclusion bodies and white matter lesions are the characteristics of this disease
.

As the disease progresses, patients may develop dementia, limb weakness, tremor, ataxia, bladder dysfunction, renal insufficiency, etc.
, which seriously affect the quality of life
.

Since the first confirmed case in China in 2017, only a few hundred cases have been reported so far
.

Because the patient's condition is hidden, the clinical manifestations are diverse, and the images are similar to cerebrovascular diseases, leading to delays in diagnosis and treatment, and the pathogenesis of the disease is unclear
.

Recently, the team of Professor Wang Xin from the Department of Neurology, Zhongshan Hospital of Fudan University discovered that a previously unrecognized abnormal polyglycine protein (polyg) aggregation is the key mechanism of adult-type neuronal nuclear inclusion disease
.

The research results have recently been published online in the top journal of neurology-Acta neuropathologica (acta neuropathologica, if=17).
Professor Wang Xin and Professor Ding Jing are the corresponding authors of the paper, and Dr.
Zhong Shaoping is the first author
.

Chief Physician Ji Yuan of the Department of Pathology and Deputy Chief Physician Ji Jun of the Department of Nephrology also participated in the study
.

In 2019, Chinese and Japanese scholars successively discovered that the ggc trinucleotide repeat amplification in the non-coding region of the notch2nlc gene is the genetic cause of adult-type neuronal nuclear inclusion disease
.

However, it is still unclear how trinucleotide repeat amplification causes characteristic inclusion body formation and imaging changes and neurodegeneration.

.

Through in-depth analysis of the notch2nlc gene, the Zhongshan Hospital team found that this repetitive sequence is located in a tiny reading frame upstream of the gene that has not been annotated
.

Through the upstream reading frame (uorf) mechanism, the ggc trinucleotide repeat is translated into a polyglycine protein (n2nlcpolyg), which corrects the traditional understanding of the protein encoded by the notch2nlc gene
.

To evaluate the effect of the number of ggc trinucleotide repeats on this pathogenic protein, the team constructed a series of plasmid-transfected cells with different repeat numbers
.

The study found that under normal conditions without ggc repeat amplification, n2nlcpolyg degrades quickly in the body without aggregation; while the patient’s repeat amplification of ggc increases the number of glycines and significantly enhances the stability and spontaneous aggregation of n2nlcpolyg.
Lead to the formation of inclusion body-like abnormal protein aggregation
.

The study also observed the dynamic occurrence and change of polyg inclusion bodies in vitro through live cell imaging technology for the first time
.

Polyg inclusion bodies: green.
The study further carried out immunostaining in patient tissues and found that n2nlcpolyg was co-labeled with nuclear inclusion markers such as p62/ubiquitin, and a number of experiments proved that n2nlcpolyg is a key factor in the formation of nuclear inclusion bodies.

.

The study also found that n2nlcpolyg interferes with the nuclear-cytoplasmic transport process, which may be the mechanism that causes nerve cell damage and neurodegeneration
.

All in all, the study found that the amplification of the notch2nlc gene ggc can translate and produce abnormal polyg protein.
This protein aggregation and deposition in the body is the main mechanism for the formation of nuclear inclusion bodies in niid patients
.

It is worth noting that previous studies have found that another ggc trinucleotide repeat amplification neurodegenerative disease, fragile x-related tremor-ataxia syndrome, also has polyg pathogenic protein deposition.

.

Therefore, niid is the second proven polyg protein disease
.

This study and another study on niid published in neuron earlier this year by professor nicolas charlet-berguerand of the French igbmc institute pointed out that polyg protein may be a common pathogenic factor of ggc trinucleotide duplication disease, and proposed a polyg disease spectrum Concept
.

Unlike the French team, the Zhongshan team also found that uorf upstream of the notch2nlc gene significantly inhibited the translation of its downstream coding region, and polyg interfered with the nuclear-cytoplasmic transport process
.

This study combines basic scientific research and clinical pathology to provide a scientific and powerful explanation for the disease mechanism of niid.
The research results will help to find specific therapeutic targets for the disease
.

Although there is still a lack of means to cure niid, active treatment can still control and delay the progression of the disease and improve the quality of life of patients
.

Zhongshan Hospital has opened an outpatient clinic for intelligent diagnosis and treatment of brain diseases, dedicated to identifying cerebrovascular diseases and abnormal causes of leukoencephalopathy, combining intelligent technology applications to improve the early detection of diseases with special causes, and clearing through the multidisciplinary team "Clinical-Imaging-Pathology-Gene" Diagnose, establish a comprehensive diagnosis and treatment plan, and provide patients with individualized and high-quality medical services
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Source: Zhongshan Hospital Affiliated to Fudan University 2020 Hot Article Selection 1.
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