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.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive degeneration of motor neurons in spinal cord, brainstem and cerebral cortex and of their corresponding axons in the corticospinal tract and in peripheral nerves
amyotrophic lateral sclerosis (ALS) can be caused by mutations in more than 20 genes, including the major ones SOD1, TARDBP (TDP-43), FUS and C9ORF72, or manifest as apparently sporadic form
TBCE is expressed at high levels in motor neurons (Schaefer et al, 2007) where it is associated to the cis-Golgi (Figure 1B) and is critical for the polymerization of Golgi-derived microtubules (Bellouze et al, 2014)
Summary
Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive degeneration of motor neurons in spinal cord, brainstem and cerebral cortex and of their corresponding axons in the corticospinal tract and in peripheral nerves. In motor neurons of ALS patients, the Golgi apparatus often appears either fragmented, i.e., transformed into multiple disconnected elements or tubular-vesicular clusters, or atrophied, i.e., reduced in its membrane content (Mourelatos et al, 1990; Gonatas et al, 1992). These pathological changes are detectable in all types of motor neurons located in spinal cord, brainstem and cerebral cortex (Mourelatos et al, 1996; Fujita et al, 1999, 2000).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
