2. Academic Validation
  3. Identification of the common neurobiological process disturbed in genetic and non-genetic models for autism spectrum disorders

Identification of the common neurobiological process disturbed in genetic and non-genetic models for autism spectrum disorders

  • Cell Mol Life Sci. 2022 Nov 13;79(12):589. doi: 10.1007/s00018-022-04617-3.
Sigita Malijauskaite # 1 2,  Ann Katrin Sauer # 1 3 4,  Seamus E Hickey 1 2,  Marco Franzoni 1 2,  Andreas M Grabrucker # 5 6 7,  Kieran McGourty # 8 9 10 11
Affiliations

Affiliations

  • 1 Bernal Institute, University of Limerick, Analog Devices Building AD3-018, AD3-019, Castletroy, Limerick, V94PH61, Ireland.
  • 2 Department of Chemical Sciences, University of Limerick, Limerick, Ireland.
  • 3 Cellular Neurobiology and Neuro-Nanotechnology Lab, Department of Biological Sciences, University of Limerick, Limerick, Ireland.
  • 4 Health Research Institute (HRI), University of Limerick, Limerick, Ireland.
  • 5 Bernal Institute, University of Limerick, Analog Devices Building AD3-018, AD3-019, Castletroy, Limerick, V94PH61, Ireland. [email protected].
  • 6 Cellular Neurobiology and Neuro-Nanotechnology Lab, Department of Biological Sciences, University of Limerick, Limerick, Ireland. [email protected].
  • 7 Health Research Institute (HRI), University of Limerick, Limerick, Ireland. [email protected].
  • 8 Bernal Institute, University of Limerick, Analog Devices Building AD3-018, AD3-019, Castletroy, Limerick, V94PH61, Ireland. [email protected].
  • 9 Department of Chemical Sciences, University of Limerick, Limerick, Ireland. [email protected].
  • 10 Health Research Institute (HRI), University of Limerick, Limerick, Ireland. [email protected].
  • 11 Synthesis and Solid State Pharmaceutical Centre, University of Limerick, Limerick, Ireland. [email protected].
  • # Contributed equally.
PMID: 36371739 DOI: 10.1007/s00018-022-04617-3
Abstract

Autism spectrum disorders (ASD) are neurodevelopmental disorders. Genetic factors, along with non-genetic triggers, have been shown to play a causative role. Despite the various causes, a triad of common symptoms defines individuals with ASD; pervasive social impairments, impaired social communication, and repeated sensory-motor behaviors. Therefore, it can be hypothesized that different genetic and environmental factors converge on a single hypothetical neurobiological process that determines these behaviors. However, the cellular and subcellular signature of this process is, so far, not well understood. Here, we performed a comparative study using "omics" approaches to identify altered proteins and, thereby, biological processes affected in ASD. In this study, we mined publicly available repositories for genetic mouse model data sets, identifying six that were suitable, and compared them with in-house derived proteomics data from prenatal zinc (Zn)-deficient mice, a non-genetic mouse model with ASD-like behavior. Findings derived from these comparisons were further validated using in vitro neuronal Cell Culture models for ASD. We could show that a protein network, centered on VAMP2, STX1A, RAB3A, CPLX2, and AKAP5, is a key convergence point mediating synaptic vesicle release and recycling, a process affected across all analyzed models. Moreover, we demonstrated that Zn availability has predictable functional effects on synaptic vesicle release in line with the alteration of proteins in this network. In addition, drugs that target kinases, reported to regulate key proteins in this network, similarly impacted the proteins' levels and distribution. We conclude that altered synaptic stability and plasticity through abnormal synaptic vesicle dynamics and function may be the common neurobiological denominator of the shared behavioral abnormalities in ASD and, therefore, a prime drug target for developing therapeutic strategies.

Keywords

AKAP5; FMR1; SHANK3; Vesicle recycling; Zinc.

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