Research reportExpression of truncated presenilin 2 splice variant in Alzheimer's disease, bipolar disorder, and schizophrenia brain cortex
Introduction
The presenilin (PS) genes were identified by their association with early-onset familial Alzheimer's disease (AD). The PS proteins are required for regulated intramembranous proteolysis of the Alzheimer's disease amyloid precursor protein and of several other type I integral membrane proteins including Notch, ErbB4, and E-cadherin which are all involved in signal transduction processes [3], [13], [17]. PS also modulate the turnover of cytoplasmic β-catenin in the Wnt signalling pathway [28]. The involvement of PS proteins in signalling pathways would anticipate further linkage with other neurological disorders. Three PS1 mutations have been found associated with frontotemporal dementia (FTD) [1], [5], [24], and we found altered PS1 transcripts were associated with some cases of sporadic FTD [6].
The PS genes contain 10 coding exons [14] (depicted in Fig. 1A). Naturally occurring alternative transcripts for PS2 include splicing out of exons 3 and 4 (together) and/or of exon 8 [23]. Additional alternative transcripts of PS2 with deletion of part of exon 3 to part of exon 7 and a transcript lacking exon 4 were reported recently [29]. Study of sporadic AD brain tissue led to the description of a variant transcript lacking exon 5 (PS2V) [25] and encoding the first 119 residues of PS2 plus a newly generated sequence of five amino acids [SSMAG] as depicted in Fig. 1B. To further investigate association of this variant PS2 gene product with AD, we undertook an analysis of RNA and protein in frontal cortex from AD and controls, including neurological disorders.
Section snippets
Brain bank tissue
Human frontal cortex was obtained from the NHMRC brain bank consortium at the Department of Pathology of the University of Melbourne (Brain Bank 1) that had been well characterized pathologically and clinically (8–88 h post-mortem delay); one hemisphere was fixed in formalin for pathological characterization while the other hemisphere was frozen and kept at −70 °C. AD cases were classified according to CERAD criteria [18]. Frontal cortex tissue was also obtained from the Mental Health Research
Detection of PS2 variant transcript by RT-PCR
RNA extracts of frontal cortex from control, AD, and other neurological disorders were analysed using primers designed to allow detection of PS2V, a PS2 transcript previously identified in AD brain [25]. Full-length PS2 transcript corresponding to 780 bp was detected in all samples. The alternate transcript lacking exon 5 (638 bp) was only detected in two cases from Brain Bank 1, one control and one Down's syndrome case. RNA was also analysed in cortex from Brain Bank 2 that included controls
Discussion
We have investigated the expression of the truncated PS2 RNA transcript, PS2V, in tissue from two brain bank collections. RT-PCR indicated that the variant mRNA transcript was present in most cortex samples from Brain Bank 2 which included controls and SZ cases, whereas it was undetectable in most samples from Brain Bank 1 that included controls and AD. The transcript was only detected in one control case and in one Down's syndrome case from Brain Bank 1. Very high levels of PS2V protein were
Acknowledgements
The work was supported by the Australian NHMRC Grant 114132. We thank Dr. Christian Czech for antibodies and Dr. Damian Holsinger for helpful discussions.
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2010, Biological PsychiatryCitation Excerpt :Significant differences have been observed in the function of CREB targets unique to the frontal cortex versus the striatum (56): those unique to the frontal cortex were relatively enriched in the presenilin pathway implicated in cognition and neurodegeneration. Whether such a pathway could play a role in impaired impulse control is highly speculative, although increases in a truncated presenilin protein were observed in postmortem frontal cortex samples from some bipolar disorder patients (57). Despite the extensive pharmacologic characterization of the 5CSRT, only a limited number of systemically administered compounds have been found to increase premature responding: the psychostimulant drugs cocaine and d-amphetamine, the selective 5-HT2C receptor agonist SB242,084, and the glutamate N-methyl-D-aspartate receptor antagonists dizocilpine and Ro 63-1908 (45,58,59); yet these drugs operate through very different pharmacologic mechanisms.