Alsin/Rac1 signaling controls survival and growth of spinal motoneurons

Jacquier, Arnaud; Buhler, Emmanuelle; Schäfer, Michael K. E.; Bohl, Delphine; Blanchard, Stéphane; Béclin, Christophe; Haase, Georg

doi:10.1002/ana.20886

Cited by 79 publications

(59 citation statements)

References 59 publications

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“…Recently, RNAi mediated alsin knockdown in motorneurons has been shown to induce cell death and to inhibit axon growth in the surviving neurons. Both cellular phenotypes were mimicked by expression of a dominant-negative Rac1 mutant and were completely blocked by expression of a constitutive-active Rac1 mutant [40]. These observations suggest that alsin signaling can contribute to the disease of ALS by its unique dual exchange factor activity that may couple endocytosis (via Rab5 activation) to cytoskeletal modulation (via Rac1 activation).…”

Section: Alsinmentioning

confidence: 79%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3 % of children and young adults. MR has been consistently associated with changes in dendrites and dendritic spine structure. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to be the underlying cause of cognitive disabilities observed in MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore naturally attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. In support of this, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotropic lateral sclerosis (ALS). Here we will discuss Rho GTPase related genes and their signaling pathways involved in MR and ALS.

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Section: Alsinmentioning

confidence: 79%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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“…Expression vectors for GFP-TBCE, hemagglutinin-TBCE, and FLAG-TBCE were generated by subcloning mouse wild-type TBCE cDNA using pCAGGS-GFP (Jacquier et al, 2006) or pCMV-Tag1 vectors (Stratagene, La Jolla, CA) as backbone. The GFP-␣-tubulin expression vector was generated by subcloning a fragment from pAcGFP1-tubulin (Clontech) into pCAGGS (Jacquier et al, 2006). Small interference RNAs (siRNAs) against luciferase or TBCE were from Dharmacon (Chicago, IL).…”

Section: Methodsmentioning

confidence: 99%

Progressive Motor Neuronopathy: A Critical Role of the Tubulin Chaperone TBCE in Axonal Tubulin Routing from the Golgi Apparatus

Schaefer¹,

Schmalbruch²,

Buhler³

et al. 2007

J. Neurosci.

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Axonal degeneration represents one of the earliest pathological features in motor neuron diseases. We here studied the underlying molecular mechanisms in progressive motor neuronopathy ( pmn) mice mutated in the tubulin-specific chaperone TBCE. We demonstrate that TBCE is a peripheral membrane-associated protein that accumulates at the Golgi apparatus. In pmn mice, TBCE is destabilized and disappears from the Golgi apparatus of motor neurons, and microtubules are lost in distal axons. The axonal microtubule loss proceeds retrogradely in parallel with the axonal dying back process. These degenerative changes are inhibited in a dose-dependent manner by transgenic TBCE complementation that restores TBCE expression at the Golgi apparatus. In cultured motor neurons, the pmn mutation, interference RNA-mediated TBCE depletion, and brefeldin A-mediated Golgi disruption all compromise axonal tubulin routing. We conclude that motor axons critically depend on axonal tubulin routing from the Golgi apparatus, a process that involves TBCE and possibly other tubulin chaperones.

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“…Linseman@va.gov. dent prosurvival signaling in primary motor neurons (7). Collectively, these findings implicate Rac as a crucial mediator of neuronal survival and suggest that disruption of Rac activity may contribute to the progression of neurodegenerative disorders.…”

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confidence: 73%

“…We have shown previously that the function of Rac is essential for the survival of cerebellar granule neurons (CGNs) 3 as the inhibition of Rac with either large clostridial cytotoxins or overexpression of a dominant negative Rac mutant induces mitochondrially dependent apoptosis of these cells (6). In a similar manner, use of either dominant negative Rac or siRNA against the Rac guanine nucleotide exchange factor alsin (ALS2) results in apoptosis of primary cultured spinal motor neurons (7). The critical role of Rac in neuronal survival is further evidenced by the finding that ALS2 is mutated in juvenile onset amyotrophic lateral sclerosis.…”

mentioning

confidence: 99%