Microtubules in health and degenerative disease of the nervous system

Abstract

Microtubules are essential for the development and maintenance of axons and dendrites throughout the life of the neuron, and are vulnerable to degradation and disorganization in a variety of neurodegenerative diseases. Microtubules, polymers of tubulin heterodimers, are intrinsically polar structures with a plus end favored for assembly and disassembly and a minus end less favored for these dynamics. In the axon, microtubules are nearly uniformly oriented with plus ends out, whereas in dendrites, microtubules have mixed orientations. Microtubules in developing neurons typically have a stable domain toward the minus end and a labile domain toward the plus end. This domain structure becomes more complex during neuronal maturation when especially stable patches of polyaminated tubulin become more prominent within the microtubule. Microtubules are the substrates for molecular motor proteins that transport cargoes toward the plus or minus end of the microtubule, with motor-driven forces also responsible for organizing microtubules into their distinctive polarity patterns in axons and dendrites. A vast array of microtubule-regulatory proteins impart direct and indirect changes upon the microtubule arrays of the neuron, and these include microtubule-severing proteins as well as proteins responsible for the stability properties of the microtubules. During neurodegenerative diseases, microtubule mass is commonly diminished, and the potential exists for corruption of the microtubule polarity patterns and microtubule-mediated transport. These ill effects may be a primary causative factor in the disease or may be secondary effects, but regardless, therapeutics capable of correcting these microtubule abnormalities have great potential to improve the status of the degenerating nervous system.

dTACC restricts bouton addition and regulates microtubule organization at the Drosophila neuromuscular junction

“…A major target and effector of these signaling networks is the presynaptic microtubule (MT) cytoskeleton (Broadie & Richmond, ; Menon, Carrillo, & Zinn, ; Ruiz‐Cañada & Budnik, ). MTs have been linked to numerous neurodevelopmental and neurodegenerative disorders (Bodaleo & Gonzalez‐Billault, ; Goellner & Aberle, ; Lasser, Tiber, & Lowery, ; Matamoros & Baas, ). However, despite the clear importance of synaptic MTs, our understanding of their regulation and function still lags behind our comprehension of the upstream signaling pathways that orchestrate synapse development.…”

Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

“…Microtubules establish the polarized architecture of neurons and serve as tracks for microtubule motor proteins as they carry proteins and lipids to where they are needed for proper neuronal function. Thus, defects in microtubule dynamics and organization underly a wide array of neurological and neuropsychiatric disorders (Matamoros & Baas, 2016; Muñoz-Lasso, Romá-Mateo, Pallardó, & Gonzalez-Cabo, 2020; Sleigh, Rossor, Fellows, Tosolini, & Schiavo, 2019).…”

Precision genetic cellular models identify therapies protective against endoplasmic reticulum stress

“…Loss of microtubule mass or altered microtubule dynamics in axons and dendrites are major contributors to neurodegenerative diseases such as ALS, Parkinson's disease, Alzheimer's disease, and several tauopathies (59). A recent screen of a ~100 small molecules identified compounds protective of ER stress in a chemicallyinduced ER stress model of ALS (SOD1 G93A ) neurodegeneration (60).…”