Dynein is a large motor protein complex that transports cargo along microtubules toward the minus end, powering retrograde axonal transport from nerve terminals to cell bodies. It is essential for neuronal survival, synaptic function, and clearance of misfolded proteins.
Dynein is a ~1.5 MDa multi-subunit complex consisting of:
- Dynein Heavy Chain (DYNC1H1): ~500 kDa motor ATPase that binds microtubules
- Dynein Intermediate Chain (DYNC1I1/DYNC1I2): scaffold for regulatory subunits
- Dynein Light Intermediate Chain (DYNC1LI1/DYNC1LI2): links to cargo
- Dynein Light Chain (DYNLT1/DYNLRB1): regulatory functions
The complex associates with dynactin (p150^Glued) for processivity and cargo binding.
In neurons, dynein powers:
- Retrograde transport of synaptic vesicles, organelles, and signaling complexes
- Transport of neurotrophic factors from synapses to cell bodies
- Late endosome and lysosome trafficking
- Nuclear transport of transcription factors
- Mitotic spindle orientation in neural progenitors
Dynein dysfunction impairs retrograde transport, leading to:
- Accumulation of organelles and proteins in distal axons
- Synaptic degeneration due to deficient replenishment
- Disrupted signaling between synapses and nuclei
- ALS: Mutations in DYNC1H1 cause dominant axonal Charcot-Marie-Tooth disease with neuronal involvement
- Alzheimer's Disease: Dynein dysfunction contributes to amyloid-beta transport deficits and tau pathology spread
- Parkinson's Disease: Impaired dynein-mediated transport affects alpha-synuclein clearance
- Huntington's Disease: Mutant huntingtin disrupts dynein-dynactin function
- Spinal Muscular Atrophy: SMN deficiency affects dynein-mediated transport
Enhancing dynein function or axonal transport is being explored as a therapeutic strategy for neurodegenerative diseases.
- Dynactin (DCTN1): Essential cofactor for processive movement
- BICD2: Adaptor protein linking cargo to dynein
- Rab proteins: Regulate cargo-specific recruitment
- Lis1/Ndel1: Regulate dynein activity and microtubule binding