Abstract
Rett (RTT) syndrome is a severe neurological disorder that affects almost exclusively females. Several detectable mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) are responsible for the onset of the disease. MeCP2 is a key transcription regulator involved in gene silencing via methylation-dependent remodeling of chromatin. Recent data highlight that lipid metabolism is perturbed in brains and livers of MECP2-null male mice. In addition, altered plasma lipid profile in RTT patients has been observed. Thus, the aim of the work is to investigate the protein network involved in cholesterol homeostasis maintenance on freshly isolated fibroblasts and plasma from both RTT and healthy donors. To this end, protein expression of 3-hydroxy-3methyl glutaryl Coenzyme A reductase (HMGR), sterol regulatory element binding proteins (SREBPs), low density lipoprotein receptor (LDLr) and scavenger receptor B-1 (SRB-1) was assessed in cultured skin fibroblasts from unaffected individuals and RTT patients. In addition, lipid profile and the abundance of proprotein convertase subtilisin/kexin type 9 (PCSK9) were analyzed on plasma samples. The obtained results demonstrate that the main proteins belonging to cholesterol regulatory network are altered in RTT female patients, providing the proof of principle that cholesterol metabolism may be taken into account as a new target for the treatment of specific features of RTT pathology.
Highlights
Rett syndrome (RTT) is (OMIM ID: 312750) a severe neurological disorder that affects almost exclusively females, with a frequency of approximately 1:10,000 live births [1]
This finding is in accordance with a recent published work, which highlighted that low density lipoprotein (LDL) concentration is significantly elevated in Mecp2-null mice [10]
high density lipoprotein (HDL) content is shown to be increased in RTT, further supporting other recent and published data [9]
Summary
Rett syndrome (RTT) is (OMIM ID: 312750) a severe neurological disorder that affects almost exclusively females, with a frequency of approximately 1:10,000 live births [1]. This disorder was first recognized about 50 years ago by Andreas Rett [2]. In 1999 mutations in the gene Methyl-CpG-binding protein 2 (MECP2) were identified as the cause of this pathology [3]. Several mutations in the X-linked MECP2 gene are detectable, leading to wide genetical and phenotypical heterogeneity of the disease [4]. MeCP2, a key transcriptional regulator, is critically involved in gene silencing through methylation-dependent remodeling of chromatin structure [5,6]. 80% of RTT clinical cases show a typical clinical picture, characterized by loss of acquired cognitive, social, and motor skills in a typical four-stage neurological regression, together with development of autistic behavior [4]
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