Autism Spectrum Disorder- and/or Intellectual Disability-Associated Semaphorin-5A Exploits the Mechanism by Which...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Autism spectrum disorder (ASD) is a neurodevelopmental condition with complex genetic underpinnings affecting neuronal morphogenesis.
• The precise molecular mechanisms driving abnormal neuronal development in ASD remain incompletely understood.

Purpose of the Study:

• To investigate the role of Rac1 guanine-nucleotide exchange factor (GEF) Dock5 signalosome molecules in neuronal process elongation.
• To elucidate the involvement of Dock5 in ASD and intellectual disability (ID)-associated Semaphorin-5A (Sema5A) mutations.

Main Methods:

• Utilized the N1E-115 cell line, a model for neuronal morphological changes.
• Employed clustered regularly interspaced short palindromic repeat (CRISPR)/CasRx-based guide(g)RNA for gene knockdown.
• Investigated the impact of Dock5 and Elmo2 knockdown, and Dock5-Elmo2 interaction region transfection on process elongation and c-Jun N-terminal kinase (JNK) activation.

Main Results:

• Dock5 signalosome molecules were found to control process elongation in neuronal cells.
• Increased process elongation associated with ASD/ID-linked Sema5A p.R676C mutation was mediated by Dock5.
• Knockdown of Dock5 or Elmo2, or transfection of the Dock5-Elmo2 interaction region, ameliorated Sema5A-induced process elongation and JNK activation.

Conclusions:

• The Dock5 signalosome plays a critical role in regulating neuronal process elongation.
• Aberrant signaling within the Dock5 pathway contributes to abnormal neuronal morphogenesis in ASD and ID.
• Dock5 signalosome molecules represent potential therapeutic targets for addressing molecular and cellular defects in ASD.