KIF5A binds RNA to orchestrate synaptic mRNA localization and stress granules in ALS

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Neuronal health relies on mRNA transport and local translation for synaptic function.
• Kinesin motor proteins are involved in mRNA transport, but their direct roles as RNA-binding proteins (RBPs) are not fully understood.

Purpose of the Study:

• To investigate the direct role of the neuron-specific kinesin KIF5A as an RBP.
• To determine how KIF5A mutations associated with amyotrophic lateral sclerosis (ALS) affect its function and neuronal homeostasis.

Main Methods:

• Demonstrated direct mRNA binding by KIF5A.
• Assessed KIF5A's role in synaptic localization of ribosomal proteins.
• Analyzed the impact of ALS-linked KIF5A mutations on mRNA binding, protein localization, neuronal excitability, and stress responses.

Main Results:

• KIF5A directly binds mRNAs encoding synaptic ribosomal proteins.
• KIF5A is essential for synaptic localization of these mRNAs and maintaining synaptic composition and function.
• ALS-linked KIF5A mutations enhance mRNA binding, increase synaptic ribosomal protein accumulation, induce neuronal hyperexcitability, and impair stress responses.

Conclusions:

• KIF5A functions as a direct RBP crucial for synaptic homeostasis.
• Mutant KIF5A disrupts synaptic function through gain-of-function mechanisms affecting mRNA transport and local translation.
• This study reveals a novel role for kinesin motor proteins in mRNA regulation and neuronal stress responses.