Increased Production of β-Amyloid and Vulnerability to Endoplasmic Reticulum Stress by an Aberrant Spliced Form of Presenilin 2

Abstract

An alternative spliced form of the presinilin 2 (PS2) gene (PS2V) lacking exon 5 has previously been reported to be expressed in human brains in sporadic Alzheimer's disease (AD). PS2V encodes the amino-terminal portion of PS2, which contains residues Met 1 -Leu 119 and 5 additional amino acid residues (SSMAG) at its carboxyl terminus. Here we report that PS2V protein impaired the signaling pathway of the unfolded protein response, similarly to familial AD-linked PS1 mutants and caused significant increases in the production of both amyloid ␤ 40 and ␤ 42 . Interestingly, PS2V-encoding protein was expressed in neuropathologically affected neurons of the hippocampal CA1 region and temporal cortex in AD patients. These findings suggest that the aberrant splicing of the PS2 gene may be implicated in the neuropathology of sporadic AD.

Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease

“…Finally, cells overexpressing HMGA1a were more sensitive to endoplasmic reticulum (ER) stress (Figure 5d), as observed in the cells expressing PS2V. 12 HMGA1a binds U1 snRNP via direct interaction with the U1-70K protein…”

“…11 We showed that PS2V protein impaired the signaling pathway of the unfolded protein response, in a manner similar to familial AD-linked PS1 mutant proteins, and caused significant increases in the production of Ab protein. 12 Intriguingly, we observed PS2V-encoded aberrant proteins in fragile pyramidal cells of the hippocampal CA1 region and in cells of the cerebral cortex of sporadic AD brains. 12,13 To elucidate the mechanism of the PS2V isoform generation, we searched for the factor that specifically binds to the exon 5 sequence of PS2 pre-mRNA.…”

“…12 Intriguingly, we observed PS2V-encoded aberrant proteins in fragile pyramidal cells of the hippocampal CA1 region and in cells of the cerebral cortex of sporadic AD brains. 12,13 To elucidate the mechanism of the PS2V isoform generation, we searched for the factor that specifically binds to the exon 5 sequence of PS2 pre-mRNA. The aberrant splicing resulting in the PS2V isoform is hypoxia-inducible in cultured neuroblastoma cells.…”

“…Furthermore, we have reported that the PS2V protein indeed impaired the signaling pathway of the unfolded-protein response, as was seen with familial AD-linked PS1 mutants, 25 and caused increases in susceptibility to various ER stress, as well as significant increases in the production of both amyloid b 1-40 and b 1-42 , which is a shared characteristic of AD patients. 12 Although the detailed mechanism of PS2V-triggered AD remains to be elucidated, PS2V may be a diagnostic marker in the neuropathology of sporadic AD. In fact, our previous report indicated that PS2V protein was not detected in FAD brains and in other disease control brains (Parkinson's disease, Huntington's disease, ALS, Machado-Joseph disease, etc.).…”

“…11,12 In sporadic AD brains, a unique shorter product PS2V, which lacked exon 5, was detected along with a major RT-PCR product corresponding to the fulllength PS2 mRNA (Figure 1a). We found that SK-N-SH neuroblastoma cell line also produced a shorter PS2V isoform besides the PS2 product by hypoxia (Figure 1b).…”