Somatic APP gene recombination in Alzheimer’s disease and normal neurons

Abstract

Somatic gene recombination of amyloid precursor protein (APP) in human neurons has been identified, encompassing thousands of genomic variants occurring mosaically in normal and sporadic Alzheimer’s disease (AD) brains. Multiple sequencing strategies and junction-specific genomic in situ hybridization revealed APP recombination, lacking introns and having precise exonic junctions, termed genomic cDNAs (gencDNAs), often with multiple recombined junctions contained within a single nucleus. Most variants showed structural changes, particularly deletion of central exons with partial exons fused together, forming intra-exonic junctions, containing single nucleotide variations. APP is a causal gene mutated in forms of AD, and our studies identified variants enriched in sporadic AD neurons, including 10 mutations identical to those in published familial AD, yet arising somatically. Additional studies linked APP neuronal RNA transcription to the appearance of gencDNAs that could be preferentially transcribed to generate myriad gene variants contributing to diversity and function in the normal and diseased brain.

Splicing and neurodegeneration: Insights and mechanisms

“…With hereditability of AD estimated around 80%, genetic variation is accepted to play a large role in disease susceptibility; however, how variation affecting alternative splicing impacts AD is understudied. A first step to remedy this gap in our knowledge is the recent development of a new predictive model to identify which SNPs in splicing regulatory elements actually affect exon skipping (Lee et al, ). A new single cell approach, single‐cell isoform RNA‐seq (ScISor‐Seq), could also advance our understanding by improving detection of splice isoforms and the precise cell types expressing them (Gupta et al, ).…”

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

“…As revealed by single cell whole genome sequencing, neurons accumulate somatic single‐nucleotide variants (SNVs) as a result of active transcription or retrotransposon activity (Coufal et al., ; Kurnosov et al., ; Lodato et al., ; Muotri et al., ). Recent evidence suggests that this process could also be instrumental in the development of neurodegenerative diseases such as Alzheimer's disease (Lee et al., ). It has yet to be explored whether and to what extent this phenomenon can be recapitulated using in vitro systems such as iPSC models.…”

What viruses tell us about evolution and immunity: beyond Darwin?

“…Recently, HERV‐K has been suspected to contribute to various human diseases, such as cancer and amyotrophic lateral sclerosis, and reverse transcriptase activity, likely of retroelement origin, to Alzheimer's disease (AD) (see below).…”

“…There are more than a thousand bacterial variants with mostly unknown functions and reverse transcriptases are also abundantly expressed in marine plankton . Reverse transcriptase activity in the human brain may play a role in the development of AD, affecting the amyloid precursor protein gene ( APP ) . Recombination of the gene with different reverse transcribed “genomic cDNAs” of various full‐length or truncated spliced mRNAs was more frequently found in the brains of AD patients than in healthy controls .…”