脆性X相关震颤/共济失调综合征(FXTAS)是与FMR1前突变相关的神经退行性疾病。目前,无法确定个体前突变携带者何时以及是否会发展FXTAS。因此,为了确定早期诊断的生物标志物,发展,以及FXTAS的进展,以及相关的失调通路,我们进行了预突变携带者(PM)的血液蛋白质组学分析,作为正在进行的纵向研究的一部分,出现了两个不同的群体:那些出现FXTAS症状的人(转换器,CON)随着时间的推移(在随后的访问中)和那些没有(非转换器,NCON)。我们将这些组与年龄匹配的健康对照(HC)进行了比较。我们通过Southern印迹和PCR分析评估CGG重复等位基因大小。通过液相色谱质谱(LC-MS/MS)获得蛋白质组谱。我们在第1次访视(V1)时鉴定了HC和PM组之间的几种显着分化的蛋白质,访问2(V2),在访问之间。我们进一步报道了失调的蛋白质途径,包括鞘脂和氨基酸代谢。我们的发现与以前的研究一致,这些研究表明参与线粒体生物能学的途径,正如在其他神经退行性疾病中观察到的那样,显著改变,似乎有助于FXTAS的发展。最后,我们将随着时间的推移发展为FXTAS的PM的血液蛋白质组和最近报道的FXTAS患者的CSF蛋白质组进行了比较,发现8种显著差异表达的共同蛋白.据我们所知,这是FXTAS中纵向蛋白质组分析和独特生物标志物和失调蛋白通路鉴定的首次报道.
Fragile X-associated Tremor/Ataxia Syndrome (
FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop
FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of
FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of
FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed
FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS.