Golgi Fragmentation in ALS Motor Neurons. New Mechanisms Targeting Microtubules, Tethers, and Transport Vesicles

Abstract

Pathological alterations of the Golgi apparatus, such as its fragmentation represent an early pre-clinical feature of many neurodegenerative diseases and have been widely studied in the motor neuron disease amyotrophic lateral sclerosis (ALS). Yet, the underlying molecular mechanisms have remained cryptic. In principle, Golgi fragmentation may result from defects in three major classes of proteins: structural Golgi proteins, cytoskeletal proteins and molecular motors, as well as proteins mediating transport to and through the Golgi. Here, we present the different mechanisms that may underlie Golgi fragmentation in animal and cellular models of ALS linked to mutations in SOD1, TARDBP (TDP-43), VAPB, and C9Orf72 and we propose a novel one based on findings in progressive motor neuronopathy (pmn) mice. These mice are mutated in the TBCE gene encoding the cis-Golgi localized tubulin-binding cofactor E, one of five chaperones that assist in tubulin folding and microtubule polymerization. Loss of TBCE leads to alterations in Golgi microtubules, which in turn impedes on the maintenance of the Golgi architecture. This is due to down-regulation of COPI coat components, dispersion of Golgi tethers and strong accumulation of ER-Golgi SNAREs. These effects are partially rescued by the GTPase ARF1 through recruitment of TBCE to the Golgi. We hypothesize that defects in COPI vesicles, microtubules and their interaction may also underlie Golgi fragmentation in human ALS linked to other mutations, spinal muscular atrophy (SMA), and related motor neuron diseases. We also discuss the functional relevance of pathological Golgi alterations, in particular their potential causative, contributory, or compensatory role in the degeneration of motor neuron cell bodies, axons and synapses.

Keywords: ALS; C9orf72; Golgi fragmentation; SOD1; TBCE; TDP-43; microtubules; neurodegeneration.

Figure 1

The Golgi apparatus in wild type motor neurons. (A) An electron micrograph showing part of the typical Golgi ribbon in a mouse lumbar spinal cord motor neuron. (B) Schematic representation of some of the molecular players involved in the organization of the wild type Golgi. Polymerization of microtubules (MT) at the cis-Golgi depends on TBCE which mediates cross talk with ARF1-mediated COPI vesicle biogenesis [box 1]. Golgi microtubules nucleated by GCC185/CLASPs at the trans-Golgi play a role in Golgi ribbon linking [box 2]. The formation of the Golgi ribbon at the cis side is mediated by the tethering complex GRASP65/GM130 [box 3]. COPI vesicle fusion is mediated by the tethering complex p115/GM130 and SNARE complexes containing GS15, GS28, and Syntaxin 5 [box4].

Figure 2

The fragmentation of the Golgi apparatus in pmn motor neurons. (A) An electron micrograph showing vesiculation of the Golgi stack in a lumbar spinal cord motor neuron from a pmn mouse aged 35 days. (B) Schematic representation of the molecular defects leading to Golgi fragmentation. Loss of TBCE function impedes polymerization of microtubules at the cis-Golgi [box 1] and potentially also their GCC185/CLASP-dependent nucleation at the trans-Golgi [box 2]. Levels of β-COP and ε-COP are reduced [box 1], vesicles containing high amounts of Golgi SNAREs GS15 and GS28 accumulate [box3] and tethers p115 and GM130 disperse away from membranes [box 4].