Cytoplasmic dynein and its regulatory proteins in Golgi pathology in nervous system disorders

Abstract

The Golgi apparatus is a dynamic organelle involved in processing and sorting of lipids and proteins. In neurons, the Golgi apparatus is important for the development of axons and dendrites and maintenance of their highly complex polarized morphology. The motor protein complex cytoplasmic dynein has an important role in Golgi apparatus positioning and function. Together, with dynactin and other regulatory factors it drives microtubule minus-end directed motility of Golgi membranes. Inhibition of dynein results in fragmentation and dispersion of the Golgi ribbon in the neuronal cell body, resembling the Golgi abnormalities observed in some neurodegenerative disorders, in particular motor neuron diseases. Mutations in dynein and its regulatory factors, including the dynactin subunit p150Glued, BICD2 and Lis-1, are associated with several human nervous system disorders, including cortical malformation and motor neuropathy. Here we review the role of dynein and its regulatory factors in Golgi function and positioning, and the potential role of dynein malfunction in causing Golgi apparatus abnormalities in nervous system disorders.

LIS1 regulates cargo-adapter–mediated activation of dynein by overcoming its autoinhibition in vivo

“…Cytoplasmic dynein-1 (called dynein hereafter) is a microtubule (MT) motor that transports a variety of cargos in eukaryotic cells, and defects in dynein-mediated transport are linked to devastating neurodegenerative diseases and brain developmental disorders (Maday et al, 2014;Jaarsma and Hoogenraad, 2015;Bertipaglia et al, 2018). The dynein-cargo interaction requires the multicomponent dynactin complex as well as specific cargo adapters (Schroer, 2004;Akhmanova and Hammer, 2010;Fu and Holzbaur, 2014;Reck-Peterson et al, 2018;.…”

Golgi ribbon disassembly during mitosis, differentiation and disease progression

“…Similarly, a mouse model with impaired dynein/dynactin function exhibited a fragmented Golgi and developed ALS-like phenotypes [118,119], corroborating that Golgi ribbon disruption induced by cytoskeletal alterations are associated with various neurodegenerative disorders [120]. …”

Insights into LIS1 function in cargo-adapter-mediated dynein activation in vivo

“…Cytoplasmic dynein-1 (called "dynein" hereafter) is a microtubule motor that transports a variety of cargos in eukaryotic cells, and defects in dynein-mediated transport is linked to devastating neurodegenerative diseases and brain developmental disorders (Maday et al, 2014;Jaarsma and Hoogenraad, 2015;Bertipaglia et al, 2018). The dynein-cargo interaction requires the multi-component dynactin complex as well as specific cargo adapters (Schroer, 2004;Akhmanova and Hammer, 2010;Fu and Holzbaur, 2014;Reck-Peterson et al, 2018;.…”