GSNgene frameshift mutations in Alzheimer’s disease

Abstract

BackgroundThe pathogenic missense mutations of the gelsolin (GSN) gene lead to familial amyloidosis of the Finnish type (FAF); however, our previous study identifiedGSNframeshift mutations existed in patients with Alzheimer’s disease (AD). TheGSNgenotype–phenotype heterogeneity and the role ofGSNframeshift mutations in patients with AD are unclear.MethodIn total, 1192 patients with AD and 1403 controls were screened through whole genome sequencing, and 884 patients with AD were enrolled for validation. Effects ofGSNmutations were evaluated in vitro. GSN, Aβ42, Aβ40 and Aβ42/40 were detected in both plasma and cerebrospinal fluid (CSF).ResultsSix patients with AD withGSNP3fs and K346fs mutations (0.50%, 6/1192) were identified, who were diagnosed with AD but not FAF. In addition, 13 patients with AD withGSNframeshift mutations were found in the validation cohort (1.47%, 13/884). Further in vitro experiments showed that both K346fs and P3fs mutations led to theGSNloss of function in inhibiting Aβ-induced toxicity. Moreover, a higher level of plasma (p=0.001) and CSF (p=0.005) GSN was observed in AD cases than controls, and a positive correlation was found between the CSF GSN and CSF Aβ42 (r=0.289, p=0.009). Besides, the GSN level was initially increasing and then decreasing with the disease course and cognitive decline.ConclusionsGSNframeshift mutations may be associated with AD. An increase in plasma GSN is probably a compensatory reaction in AD, which is a potential biomarker for early AD.

Molecular clues unveiling spinocerebellar ataxia type-12 pathogenesis

“…Also, GSN is observed to have reduced expression in advanced disease states of Alzheimer, leading to exacerbation of disease. 29 Similarly, S100A6 (calcyclin or calmodulin-like protein 3) is a member of the S100 family of calcium-binding proteins whose expression level has been observed to be altered in Alzheimer disease, Parkinson disease, ALS, and HD. Recently, its role has been discovered in the differentiation of astrocytes.…”

Protein profiling and assessment of amyloid beta levels in plasma in canine refractory epilepsy

“…In addition, gelsolin m expression was lower in the hippocampus of mice with epilepsy and seizures than in mice without seizures ( 69 ). Gelsolin is also considered to be involved in AD and the regulation of Aβ levels according to the finding that diverse gelsolin alterations are connected with the progression of AD ( 70 , 71 ). Gelsolin administration or overexpression induced a considerable reduction in the amyloid burden and Aβ level in AD transgenic mice ( 70 , 72 ).…”

“…Greater plasma and CSF gelsolin concentrations were detected in patients with AD than in controls, and a positive association was found between gelsolin and Aβ 42 levels in CSF. The increase in plasma gelsolin levels is most likely a compensatory reaction in AD ( 71 ).…”

Exosomes in the Diagnosis of Neuropsychiatric Diseases: A Review

“…Aβ processing and synthesis-associated proteins are also potential markers for the diagnosis of AD. A disintegrin and metalloproteinase (ADAM10) is the major α-secretase in APP processing and prevents the accumulation of Aβ in neurons [ 91 ]; gelsolin (GSN) is an Aβ-binding that prevents Aβ aggregation [ 92 ]; insulin-like growth factor 1 (IGF-1) induces the release of neuron-bound Aβ oligomers and inhibits Tau phosphorylation [ 93 , 94 ]. These proteins are significantly reduced in exosomes from different sources of AD patients [ 89 , 95 , 96 ].…”