RNA-Seq reveals autism-related mutations in aging brains of Alzheimer’s patients

Significant overlap found between Alzheimer’s-related mutations and those producing autism and related intellectual disabilities, TAU researchers say

Researchers believe that autism is caused by mutations that occur sporadically in the egg or sperm or during pregnancy. Activity-dependent neuroprotective protein (ADNP) is a dominant gene whose de novo (during pregnancy) mutations are known to cause autism-related intellectual disabilities. A new Tel Aviv University study has found that ADNP mutations continue to occur in old age and accumulate in the brains of Alzheimer’s disease patients.

“We discovered thousands of mutations in aging human brains, especially in the individual Alzheimer’s brains,” explains Prof. Gozes. “We were surprised to find a significant overlap in Alzheimer’s genes undergoing mutations with genes that impact autism, intellectual disability and mechanisms associated with the cell skeleton/transport system health. Importantly, the cell skeleton/transport system includes the protein Tau, one of the major proteins affected in Alzheimer’s disease, which form the toxic neurofibrillary tangles.”

The protein ADNP was first discovered in Prof. Gozes’s laboratory at TAU 20 years ago. Postmortem studies have indicated that it undergoes mutations in the aging Alzheimer’s brain.

“Brain changes associated with Alzheimer’s disease may begin 20 or more years before any symptoms appear,” adds Prof. Gozes. “As neuronal damage increases, the brain can no longer compensate for the changes, and individuals show cognitive decline. Currently, the diagnosis of Alzheimer’s occurs when the brain damage of individual patients is already widespread, so that current drugs can at most offer symptomatic relief. But they provide no cure.”

In their new study, Prof. Gozes and her group propose a paradigm-shifting concept in the understanding of Alzheimer’s disease. According to the research, accumulating mosaic somatic mutations — uninherited genetic alterations passed on during cell division — promote brain pathology. This could provide an avenue toward developing new diagnostic measures and therapies.

Through a complete sequencing of protein encoding DNA (a technique called RNA-sequencing) and further bioinformatics analysis, the team identified thousands of mutations in the aging Alzheimer’s brain. Further sophisticated cell cultures and live cell imaging technologies allowed for the identification of protective molecules that could serve as potential drug candidates.

Somatic mutations/AD—networks in the olfactory bulb (OB)

rna-seq

a Interaction network by the STRING tool for 104 mutated genes with OMIM disease association. The comparisons were made with mutated genes, including AD specific + AD-control shared mutations. Results of variant calling from RNA-Seq from 39 samples of OB indicated GO molecular enrichment-Cytoskeletal protein binding (FDR = 2E-08) colored with light purple, GO Biological process-cytoskeletal enrichment-cytoskeleton organization (FDR = 2.4E-4) colored with red/brown. GO cellular component-cytoskeleton (FDR = 8.9E-8) colored with light blue. A total of 39 genes (38%) related to the cytoskeleton OMIM-identified mutated genes. b Venn graph (http://www.interactivenn.net/) identifying genes that are shared with Autism: https://gene.sfari.org/database/human-gene/ and ID: http://www.ccgenomics.cn/IDGenetics/gene.php?dataset=IDGD_gene_detail and http://gfuncpathdb.ucdenver.edu/iddrc/iddrc/data/IDgenelist_gsym.html. c Shared genes described in (b) are named in table (red, AD—only mutations).

“We found in cell cultures that the ADNP-derived snippet, the drug candidate NAP, inhibited mutated-ADNP toxicity and enhanced the healthy function of Tau, a key brain protein involved in Alzheimer’s disease and other brain diseases,” says Prof. Gozes. “We hope that new diagnostics and treatment modes will be developed based on our discoveries.”

Source –  Tel Aviv University

Ivashko-Pachima Y, Hadar A, Grigg I, Korenková V, Kapitansky O, Karmon G, Gershovits M, Sayas CL, Kooy RF, Attems J, Gurwitz D, Gozes I. (2019) Discovery of autism/intellectual disability somatic mutations in Alzheimer’s brains: mutated ADNP cytoskeletal impairments and repair as a case study. Mol Psychiatry [Epub ahead of print]. [article]

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