Abstract
The aberrancy of U1 small nuclear ribonucleoprotein (snRNP) complex and RNA splicing has been demonstrated in Alzheimer’s disease (AD). Importantly, the U1 proteopathy is AD-specific, widespread and early-occurring, thus providing a very unique clue to the AD pathogenesis. The prominent feature of U1 histopathology is its nuclear depletion and redistribution in the neuronal cytoplasm. According to the preliminary data, the initial U1 cytoplasmic distribution pattern is similar to the subcellular translocation of the spliceosome in cells undergoing mitosis. This implies that the U1 mislocalization might reflect the neuronal cell cycle-reentry (CCR) which has been extensively evidenced in AD brains. The CCR phenomenon explains the major molecular and cellular events in AD brains, such as Tau and amyloid precursor protein (APP) phosphorylation, and the possible neuronal death through mitotic catastrophe (MC). Furthermore, the CCR might be mechanistically linked to inflammation, a critical factor in the AD etiology according to the genetic evidence. Therefore, the discovery of U1 aberrancy might strengthen the involvement of CCR in the AD neuronal degeneration.
Highlights
Alzheimer’s disease (AD) is the most common dementia that is caused by the aging-related irreversible progression of neurodegeneration in the brain (Goedert and Spillantini, 2006; Roberson and Mucke, 2006)
In combination with other lines of evidence from pathology (SerranoPozo et al, 2011; Selkoe, 2013), biochemistry (Cleary et al, 2005; Masters and Selkoe, 2012), cell biology (Shankar et al, 2008; Kuperstein et al, 2010) and animal models (Lesne et al, 2006; Oakley et al, 2006), it is well accepted that the amyloid cascade is the initiating event in the AD pathogenesis (Selkoe et al, 2012; Bloom, 2014; Selkoe and Hardy, 2016)
It is known that some neurodegenerative disorders are caused by the aberrancy of RNA processing proteins (Neumann et al, 2006; Sreedharan et al, 2008; Mackenzie et al, 2010), but whether the pathogenesis of AD possibly involves a similar mechanism had remained unclear, until we have found the U1 small nuclear ribonucleoprotein complex pathology and the RNA splicing deficiency in AD patents (Bai et al, 2013)
Summary
Alzheimer’s disease (AD) is the most common dementia that is caused by the aging-related irreversible progression of neurodegeneration in the brain (Goedert and Spillantini, 2006; Roberson and Mucke, 2006). It is known that some neurodegenerative disorders are caused by the aberrancy of RNA processing proteins (Neumann et al, 2006; Sreedharan et al, 2008; Mackenzie et al, 2010), but whether the pathogenesis of AD possibly involves a similar mechanism had remained unclear, until we have found the U1 small nuclear ribonucleoprotein (snRNP) complex pathology and the RNA splicing deficiency in AD patents (Bai et al, 2013). These proteins are aggregated and form tangle-like structures in the neuronal cytoplasm in AD brains (Bai et al, 2013; Hales et al, 2014a).
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