{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T16:59:00Z","timestamp":1777395540135,"version":"3.51.4"},"reference-count":107,"publisher":"SAGE Publications","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2021,6,29]]},"abstract":"<jats:p>Background: The most common cause of early-onset familial Alzheimer\u2019s disease (EOfAD) is mutations in PRESENILIN 1 (PSEN1) allowing production of mRNAs encoding full-length, but mutant, proteins. In contrast, a single known frameshift mutation in PSEN1 causes familial acne inversa (fAI) without EOfAD. The molecular consequences of heterozygosity for these mutation types, and how they cause completely different diseases, remains largely unexplored. Objective: To analyze brain transcriptomes of young adult zebrafish to identify similarities and differences in the effects of heterozygosity for psen1 mutations causing EOfAD or fAI. Methods: RNA sequencing was performed on mRNA isolated from the brains of a single family of 6-month-old zebrafish siblings either wild type or possessing a single, heterozygous EOfAD-like or fAI-like mutation in their endogenous psen1 gene. Results: Both mutations downregulate genes encoding ribosomal subunits, and upregulate genes involved in inflammation. Genes involved in energy metabolism appeared significantly affected only by the EOfAD-like mutation, while genes involved in Notch, Wnt and neurotrophin signaling pathways appeared significantly affected only by the fAI-like mutation. However, investigation of direct transcriptional targets of Notch signaling revealed possible increases in \u03b3-secretase activity due to heterozygosity for either psen1 mutation. Transcriptional adaptation due to the fAI-like frameshift mutation was evident. Conclusion: We observed both similar and contrasting effects on brain transcriptomes of the heterozygous EOfAD-like and fAI-like mutations. The contrasting effects may illuminate how these mutation types cause distinct diseases.<\/jats:p>","DOI":"10.3233\/jad-210128","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T13:22:07Z","timestamp":1621603327000},"page":"327-347","source":"Crossref","is-referenced-by-count":11,"title":["PRESENILIN 1 Mutations Causing Early-Onset Familial Alzheimer\u2019s Disease or Familial Acne Inversa Differ in Their Effects on Genes Facilitating Energy Metabolism and Signal Transduction"],"prefix":"10.1177","volume":"82","author":[{"given":"Karissa","family":"Barthelson","sequence":"first","affiliation":[{"name":"Alzheimer\u2019s Disease Genetics Laboratory, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide, SA, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Dong","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Genetics Laboratory, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide, SA, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgan","family":"Newman","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Genetics Laboratory, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide, SA, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Lardelli","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Genetics Laboratory, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide, SA, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-210128_ref1","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1212\/01.WNL.0000042088.22694.E3","article-title":"Early onset familial Alzheimer\u2019s disease: Mutation frequency in 31 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