Recently, the team of Professor Shen Lu from the Department of Neurology, Xiangya Hospital, Central South University (CSU) online published the latest study results in an original article entitled "GSN Gene Frameshift Mutations in Alzheimer's Disease” in the Journal of Neurology, Neurosurgery and Psychiatry owned by BMJ. This study for the first time identified a pathogenic gene GSN leading to familial amyloidosis of the Finnish type (FAF) as a novel risk gene for Alzheimer's disease (AD), and that the plasma GSN level may become a novel biomarker for AD. Dr. Jiang Yaling, Department of Neurology, Xiangya Hospital, CSU, is the first author of the article, Professor Shen Lu and Associate Researcher Jiao Bin are the co-corresponding authors, and Xiangya Hospital, CSU is the sole unit for the first author and corresponding authors.
As the most common type of senile dementia, AD has a complex pathogenesis, and genetic factors play an important role in the pathogenesis of AD. Professor Shen Lu's team used whole genome sequencing to analyze rare variants in the AD case-control cohort (1192 AD patients and 1403 controls), and found that the GSN frameshift mutations accounted for a relatively large proportion of AD patients (0.50%, 6/1192); subsequently, GSN-targeted sequencing in the validation cohort found that the frequency of GSN frameshift mutations in AD patients was as high as 1.47%. GSN gene encoded gelsolin is a calcium-regulated actin regulatory protein involved in multiple physiological processes such as inflammation, cell activity, apoptosis, and carcinogenesis. It was previously found that pathogenic missense mutations in the GSN gene can lead to FAF, and its main manifestations were corneal lattice dystrophy, cranial neuropathy, peripheral neuropathy, and skin laxity, which were different from the clinical phenotypes of AD. In order to clarify the clinical diagnosis of patients with GSN frameshift mutations, the team completed Aβ-PET and skin biopsy tests on some patients, and confirmed that patients with GSN frameshift mutations had an AD phenotype, not FAF. Therefore, this study for the first time identified the pathogenic gene of FAF, GSN, as a novel risk gene for AD.
Further in vitro experimental studies found that: GSN missense mutations can form gelsolin protein fragments and deposit in the corresponding tissues, leading to FAF; and GSN frameshift mutations are different, and their functions in reducing Aβ42 levels, inhibiting Aβ-induced toxicity and protecting cell apoptosis are lost, suggesting that different mutant forms of the same gene may lead to different pathogenic mechanisms and present different clinical phenotypes. To further explore whether gelsolin can be used as an early diagnostic biomarker for AD, the team also found that the levels of gelsolin in plasma and cerebrospinal fluid of AD patients were significantly higher than those of controls, which was positively correlated with the level of Aβ42 in cerebrospinal fluid; the level of gelsolin protein tended to increase and then decrease with the duration of the disease and cognitive decline, suggesting that the elevated plasma gelsolin protein may be a compensatory response to AD, and it is expected to become a novel biomarker for AD. This study for the first time clarified that the GSN gene frameshift mutation may be associated with the risk of AD, and provided a new target and new ideas for the early diagnosis and comprehensive intervention of AD.
Source: Xiangya Hospital
First review: Tang Xiaojun; Second review: Han Yan; Final review: Wang Jianxiang