Mutations in cytoplasmic dynein and its regulators cause malformations of cortical development and neurodegenerative diseases

Abstract

Neurons are highly specialized for the processing and transmission of electrical signals and use cytoskeleton-based motor proteins to transport different vesicles and cellular materials. Abnormalities in intracellular transport are thought to be a critical factor in the degeneration and death of neurons in both the central and peripheral nervous systems. Several recent studies describe disruptive mutations in the minus-end-directed microtubule motor cytoplasmic dynein that are directly linked to human motor neuropathies, such as SMA (spinal muscular atrophy) and axonal CMT (Charcot-Marie-Tooth) disease or malformations of cortical development, including lissencephaly, pachygyria and polymicrogyria. In addition, genetic defects associated with these and other neurological disorders have been found in multifunctional adaptors that regulate dynein function, including the dynactin subunit p150(Glued), BICD2 (Bicaudal D2), Lis-1 (lissencephaly 1) and NDE1 (nuclear distribution protein E). In the present paper we provide an overview of the disease-causing mutations in dynein motors and regulatory proteins that lead to a broad phenotypic spectrum extending from peripheral neuropathies to cerebral malformations.

The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation

“…Nde1 has been implicated in the regulation of the cytoskeleton and dynein motors (Lipka et al, 2013). However, it is unclear how such regulation could underlie the tissue specific and spatiotemporally dependent phenotype of both human and mouse NDE1/Nde1 mutations nor the DNA replication defects described in this study.…”

Building the Neuronal Microtubule Cytoskeleton

“…Mutations in microtubule-related genes encoding for microtubule-associated proteins (MAPs) (e.g., Tau), MT severing proteins (e.g., spastin), microtubule-based motor proteins (e.g., dynein, kinesin), and motor associated regulators (e.g., dynactin, doublecortin, and lis1) are associated with various neurodevelopmental problems (Lipka et al, 2013;Reiner and Sapir, 2013). In addition, impairment of axonal transport in mature neurons is a common factor in many of the major neurodegenerative diseases, including the motor neuron diseases amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (Millecamps and Julien, 2013) and neuroinflammatory diseases such as multiple sclerosis (Sorbara et al, 2014).…”

Bicaudal D Family Adaptor Proteins Control the Velocity of Dynein-Based Movements

“…Mammalian BICD family proteins have been implicated in Rab6 secretory vesicle trafficking (Grigoriev et al, 2007;Matanis et al, 2002) and nuclear positioning (Splinter et al, 2010). Recent studies identified various mutations in the human BICD2 gene in patients with dominant congenital spinal muscular atrophy (Lipka et al, 2013).…”