Dysfunction of endocytic kinase AAK1 in ALS

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Familial amyotrophic lateral sclerosis (ALS) is linked to mutations in superoxide dismutase 1 (SOD1).
• The precise mechanisms of mutant SOD1 toxicity in ALS pathogenesis are not fully understood.
• Identifying novel interacting proteins can elucidate new disease pathways.

Purpose of the Study:

• To identify proteins that selectively interact with mutant SOD1.
• To investigate the role of identified proteins in the pathology of SOD1-linked ALS.
• To explore the involvement of the endocytic pathway in ALS.

Main Methods:

• Yeast two-hybrid screening to identify SOD1-interacting proteins.
• Utilizing transgenic mouse and rat models of SOD1-linked familial ALS (FALS).
• Immunofluorescence and Western blot analysis to assess protein localization and levels in disease models and patient samples.

Main Results:

• Adaptor-associated kinase 1 (AAK1) was identified as a protein selectively interacting with mutant SOD1.
• In ALS models, AAK1 mislocalized to protein aggregates containing mutant SOD1 and neurofilaments.
• AAK1 levels were reduced in human ALS patients, and it showed altered colocalization with endosomal and presynaptic markers.

Conclusions:

• AAK1 is a novel interacting partner of mutant SOD1 in ALS.
• Dysregulation of AAK1 and its mislocalization indicate a role for the endosomal and synaptic vesicle recycling pathway in ALS.
• These findings suggest new therapeutic targets for familial ALS.