Microtubule-actin cross-linking factor 1, isoforms 1/2/3/4/5

MACF1 is a large cytoskeletal cross-linking protein that binds F-actin and microtubules, coordinating their organization and stability (UniProt: Q9UPN3). It regulates focal adhesion dynamics, Wnt signaling through AXIN1 translocation, and plays critical roles in cell migration, wound healing, and neurite outgrowth during brain development. The protein also facilitates vesicle transport and anchors microtubule minus-ends to actin filaments via interaction with CAMSAP3.

MACF1 is associated with Lissencephaly 9 with complex brainstem malformation (LIS9, MIM 618325), an autosomal dominant neurodevelopmental disorder characterized by cortical disorganization, developmental delay, and brainstem malformation (UniProt: Q9UPN3). Given its essential role in neuronal cytoskeletal organization and brain development, perturbations in MACF1 function have implications for neurological disease.

In Alzheimer's disease, MACF1 shows ambiguous direction of change across subcellular fractions in post-mortem AD brain versus age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of −0.25 across two analyzed fractions. This modest, inconsistent signal suggests MACF1 dysregulation may not be a primary proteomic hallmark of AD pathology, though its cytoskeletal role warrants further investigation in disease context.