Abstract
BackgroundPathological Golgi fragmentation represents a constant pre-clinical feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) but its molecular mechanisms remain hitherto unclear.ResultsHere, we show that the severe Golgi fragmentation in transgenic mutant SOD1G85R and SOD1G93A mouse motor neurons is associated with defective polymerization of Golgi-derived microtubules, loss of the COPI coat subunit β-COP, cytoplasmic dispersion of the Golgi tether GM130, strong accumulation of the ER-Golgi v-SNAREs GS15 and GS28 as well as tubular/vesicular Golgi fragmentation. Data mining, transcriptomic and protein analyses demonstrate that both SOD1 mutants cause early presymptomatic and rapidly progressive up-regulation of the microtubule-destabilizing proteins Stathmins 1 and 2. Remarkably, mutant SOD1-triggered Golgi fragmentation and Golgi SNARE accumulation are recapitulated by Stathmin 1/2 overexpression but completely rescued by Stathmin 1/2 knockdown or the microtubule-stabilizing drug Taxol.ConclusionsWe conclude that Stathmin-triggered microtubule destabilization mediates Golgi fragmentation in mutant SOD1-linked ALS and potentially also in related motor neuron diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0111-6) contains supplementary material, which is available to authorized users.
Highlights
Pathological Golgi fragmentation represents a constant pre-clinical feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) but its molecular mechanisms remain hitherto unclear
We demonstrate that Golgi membranes form a dense ribbon in the cell bodies of control and SOD1wt motor neurons, but appear fragmented or atrophied in motor neurons of mutant SOD1G85R and SOD1G93A mice (Fig. 1a)
Golgi fragmentation was confirmed by GM130 membrane modeling demonstrating an ~4 fold increase in the number of individual Golgi profiles in SOD1G85R and SOD1G93A motor neurons when compared to control (Fig. 1a,b)
Summary
Pathological Golgi fragmentation represents a constant pre-clinical feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) but its molecular mechanisms remain hitherto unclear. Structural alterations of the Golgi apparatus are among the earliest and most constant pathological features in neurodegenerative diseases and have been widely studied in the motor neuron disease amyotrophic lateral sclerosis (ALS) [16, 23, 57]. The Golgi apparatus of normal motor neurons is made of stacked membrane-bound cisternae that are laterally connected to form the Golgi ribbon [5]. Intra-Golgi transport involves COPI-coated vesicles [2] which are formed through recruitment of coatomers α-ζ [43], tethered by Rabs and Golgins [37] and fused/docked to target membranes by Golgi SNAREs [29]. The first mechanism involves an impairment in transport from endoplasmic reticulum (ER) to Golgi [4, 52] and from Golgi to plasma
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