Cytoplasmic dynein heavy chain: the servant of many masters

Abstract

HighlightsThe cytoplasmic dynein complex is the main retrograde motor in all eukaryotic cells.This complex is built around a dimer of cytoplasmic dynein heavy chains (DYNC1H1).Mouse DYNC1H1 mutants have sensory defects, but motor defects have been controversial.Now human DYNC1H1 mutations with sensory, motor, and cognitive deficits are being found.The study of these mutations will give us new insight into DYNC1H1 function in the nervous system.

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein–dynactin–cargo adaptor complexes

“…The DYNC1H1 mutant strains were identified in genetic screens due to hind limb clenching and an abnormal gait (1), suggesting parallels with the SMALED phenotype in humans. Heterozygosity for a null mutation in DYNC1H1 does not cause overt phenotypes in mice (19).…”

“…At the time of writing, more than 30 heterozygous missense mutations in the DYNC1H1 gene have been identified in patients diagnosed with spinal muscular atrophy with lower extremity predominance (SMALED) [Online Mendelian Inheritance in Man (OMIM): 158600)] or malformations of cortical development (MCD) (OMIM: 614563) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). SMALED is characterized by muscle weakness in the legs, which is caused by congenital or early childhood-onset loss of spinal cord motor neurons.…”

Uptake and transport of clostridial neurotoxins

“…Accordingly, in vivo studies using Loa mice, which carry a mutation in the cytoplasmic dyneinheavy chain, show deficits in axonal transport, and motor and sensory neuron degeneration [156]. Dynein plays a major role in regulating other motor proteins, since its inhibition alters kinesin and myosin contribution to retrograde transport [145,157]. In addition, bicaudal D homolog 1 (BICD1), an adaptor protein of the dynein-dynactin complex, has been recently shown to play a role in TeNT and NT receptor trafficking [127,158].…”

The role of axonal transport and mitochondrial dysfunction in neurodegeneration-focusing on Huntington's disease

“…Neurons are among the largest cells in humans and have extensive processes with large distances separating neuronal cell bodies from axons and synapses which makes them uniquely dependent on axonal transport Schiavo et al, 2013;Chevalier-Larsen and Holzbaur, 2006; (Pfister et al, 2006). At the core of the molecule lies a homodimer of heavy chains forming the sites of ATP binding and microtubule binding (Gee et al, 1997;Pfister et al, 2005;Gennerich et al, 2007).…”

“…Loss of dynein/dynactin function is considered an important factor in the pathogenesis of neurodegenerative diseases Schiavo et al, 2013;ChevalierLarsen and Holzbaur, 2006;Levy and Holzbaur, 2006). Impairment of retrograde axonal transport appears to be one of the earliest pathogenic changes during neurodegeneration , and transgenic inhibition of retrograde axonal transport induces the degeneration of motor neurons (LaMonte et al, 2002;Teuling et al, 2008).…”