Summary: Researchers identified autism-linked ADNP gene mutations in postmortem olfactory bulbs and hippocampi from people with Alzheimer’s disease, suggesting somatic mutations accumulate with age and may contribute to neurodegeneration.
Source: AFTAU
Overview: Scientists have long recognized that many autism spectrum disorders arise from de novo mutations occurring in the egg, sperm, or during early development. Activity-dependent neuroprotective protein (ADNP) is a dominant gene whose spontaneous mutations during pregnancy are known to cause autism-related intellectual disability. A new study from Tel Aviv University reveals that ADNP mutations also appear later in life, accumulating in the brains of people with Alzheimer’s disease (AD).
The research team was led by Prof. Illana Gozes and carried out by PhD candidates Yanina Ivashko-Pachima and Adva Hadar, with contributions from Iris Grigg, Oxana Kapitansky and Gidon Karmon. Adva Hadar was co-supervised by Prof. David Gurwitz of TAU’s Sackler Faculty of Medicine. International collaborators included laboratories from the Czech Republic, Weizmann Institute of Science, Spain, Belgium and the UK. The study was published in Molecular Psychiatry on October 30.
Prof. Gozes holds the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and directs the Elton Laboratory for Molecular Neuroendocrinology at TAU’s Department of Human and Molecular Genetics. She is also affiliated with TAU’s Adams Super Center for Brain Studies and the Sagol School of Neuroscience.
“We detected thousands of mutations in aging human brains, with particular enrichment in individual Alzheimer’s samples,” Prof. Gozes explains. “Strikingly, many of the genes mutated in AD overlap with genes implicated in autism and intellectual disability, and with pathways that maintain the cytoskeleton and intracellular transport. This convergence is meaningful because the cytoskeleton and transport machinery include Tau, a protein that aggregates into neurofibrillary tangles in Alzheimer’s disease.”
ADNP was originally identified in Prof. Gozes’s lab. Building on this background, the group performed comprehensive RNA sequencing (RNA-Seq) of protein-coding transcripts from multiple brain regions and applied bioinformatic analyses to search for somatic (post-zygotic) mutations. The team detected thousands of sequence changes in aging brains and validated specific ADNP mutations in olfactory bulb and hippocampal samples from AD patients.
Key findings included the identification of a known genomic autism-related ADNP mutation (c.2188C>T) in postmortem AD olfactory bulbs and hippocampi, and discovery via RNA-Seq of a novel ADNP hotspot mutation, c.2187_2188insA. Across all samples the researchers catalogued 665 mutations in 596 genes, with 441 mutations found in AD patients (389 genes including 38% exclusive to AD samples). Many mutated genes are listed in OMIM as disease-causing and converge on cytoskeletal processes and pathways tied to autism and intellectual disability.
Comparative analysis showed that both the number of mutations and their average frequencies per subject were higher in Alzheimer’s cases than in controls. Expanding data mining to RNA-Seq libraries from hippocampus, dorsolateral prefrontal cortex, fusiform gyrus and superior frontal gyrus (583 subjects total) yielded consistent results. In the large fusiform gyrus dataset (117 subjects) with deep coverage, the frequency of the c.2187_2188insA ADNP mutation correlated with Braak stage, indicating greater ADNP mutation burden in specimens with more advanced tauopathy.
To test functional consequences and repair strategies, the team used cultured cells and live-cell imaging. They examined the effects of mutated ADNP on the microtubule (MT) cytoskeleton and Tau–MT interactions. In these models, a short peptide derived from ADNP called NAP (also known as CP201) reduced mutated-ADNP toxicity, protected microtubules, and enhanced Tau–microtubule association, suggesting a potential protective or therapeutic action.
Prof. Gozes emphasizes the clinical implications: “Pathological processes in Alzheimer’s can begin decades before symptoms appear. If accumulating somatic mutations contribute to disease progression, they may offer new biomarkers for earlier diagnosis and novel targets for intervention. Our findings point toward a paradigm in which mosaic somatic mutations promote brain pathology over time.”
Funding: This work received partial support from the Israel Science Foundation, AMN Foundation, ERA-NET Neuron, Alicia Koplowitz Foundation, Spanish Friends of Tel Aviv University, Anne and Alex Cohen, Canadian Friends of Tel Aviv University, Drs. Ronith and Armand Stemmer and French Friends of Tel Aviv University. Additional grants from the UK, Czech Republic, Spain and the EU supported international collaborators.
Intellectual property related to using ADNP and associated mutations for Alzheimer’s diagnosis and for ADNP-derived peptides or mimetics to treat Alzheimer’s and ADNP-related autism spectrum disorders is under patent protection (I. Gozes, A. Hadar, Y. Ivashko-Pachima). Prof. Gozes serves as chief scientific officer of Coronis Neurosciences, the company developing NAP (CP201) for ADNP syndrome and related indications.
Source:
AFTAU
Media Contact:
George Hunka – AFTAU
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Public domain image.
Original Research: Open access
“Discovery of autism/intellectual disability somatic mutations in Alzheimer’s brains: mutated ADNP cytoskeletal impairments and repair as a case study”, Yanina Ivashko-Pachima, Adva Hadar, Iris Grigg, Vlasta Korenková, Oxana Kapitansky, Gidon Karmon, Michael Gershovits, C. Laura Sayas, R. Frank Kooy, Johannes Attems, David Gurwitz & Illana Gozes. Molecular Psychiatry. DOI: 10.1038/s41380-019-0563-5.
Abstract (condensed): The authors propose that de novo somatic mutations arising during life, including mutations in the ADNP gene, contribute to Alzheimer’s pathology. RNA-Seq of multiple brain regions identified hundreds of mutations enriched in AD cases and converging on cytoskeletal mechanisms and genes linked to autism and intellectual disability. Several ADNP mutations were discovered and shown in cell models to impair microtubule function; the ADNP-derived peptide NAP mitigated these effects and promoted Tau–microtubule association. The study supports a model in which accumulating mosaic somatic mutations promote neurodegeneration and suggests new avenues for diagnostics and therapeutic development.