What happens if dynein function is disrupted?
Axonal and cytoplasmic retrograde transport essential for neuronal survival autophagic clearance and degradation pathways relies on cytoplasmic dynein 1 delivering cargo to perinuclear lysosomes and Golgi apparatus clustering center. Cargo including late endosomes autophagosomes signaling endosomes carrying neurotrophins TrkB and NGF Golgi fragments and aggregated misfolded proteins move from periphery toward centrosome where microtubule minus ends anchor near nucleus. Mechanistically dynein adaptors such as BicD2 Hook1 Rab11 FIP3 recruit cargos link to dynactin Arp1 filament increasing run length. When dynein heavy chain mutated or inhibited by small molecule ciliobrevin or genetic depletion retrograde flow ceases: peripheral vesicles accumulate at cell cortex Golgi apparatus fragments and disperses throughout cytoplasm because its ribbon positioning depends on minus end directed clustering via dynein, endocytic sorting and degradation delayed, accumulation of ubiquitinated proteins leads to neurodegeneration observed in spinal muscular atrophy ALS models. Kinesin activity may increase compensatory but cannot replace retrograde polarity. Additional regulatory inputs including phosphorylation, small GTPases, and cargo adaptors fine tune filament assembly stability and motor activity matching cellular demands during division, migration, and mechanical stress responses efficiently.
Ref: Reck-Peterson et al., Nat Rev Mol Cell Biol 2018 – Dynein disruption impairs transport toward Golgi phenotype.