Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse

Schmitt-John, Thomas; Drepper, Carsten; Mussmann, Anke; Hahn, Phillip; Kuhlmann, Melanie; Thiel, Christian; Hafner, Martin; Lengeling, Andreas; Heimann, Peter; Jones, Julie Miller; Meisler, Miriam H.; Jockusch, Harald

doi:10.1038/ng1661

Cited by 209 publications

(224 citation statements)

References 14 publications

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“…According to these similarities, the acrosome has been postulated to be a modified lysosome [4]. Components of the endocytic machinery, such as Afaf [14], SH3P13 [23], SPE-39 [24], UBPy [25], RasGRF1 [26], and Vps54 [27,28], are involved in the biogenesis of the acrosome [2]. This evidence strongly supports the notion that the acrosome is a novel LRO.…”

Section: Discussionsupporting

confidence: 64%

Atg7 is required for acrosome biogenesis during spermatogenesis in mice

et al. 2014

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The acrosome is a specialized organelle that covers the anterior part of the sperm nucleus and plays an essential role in the process of fertilization. The molecular mechanism underlying the biogenesis of this lysosome-related organelle (LRO) is still largely unknown. Here, we show that germ cell-specific Atg7-knockout mice were infertile due to a defect in acrosome biogenesis and displayed a phenotype similar to human globozoospermia; this reproductive defect was successfully rescued by intracytoplasmic sperm injections. Furthermore, the depletion of Atg7 in germ cells did not affect the early stages of development of germ cells, but at later stages of spermatogenesis, the proacrosomal vesicles failed to fuse into a single acrosomal vesicle during the Golgi phase, which finally resulted in irregular or nearly round-headed spermatozoa. Autophagic flux was disrupted in Atg7-depleted germ cells, finally leading to the failure of LC3 conjugation to Golgi apparatus-derived vesicles. In addition, Atg7 partially regulated another globozoospermia-related protein, Golgi-associated PDZ-and coiled-coil motif-containing protein (GOPC), during acrosome biogenesis. Finally, the injection of either autophagy or lysosome inhibitors into testis resulted in a similar phenotype to that of germ cell-specific Atg7-knockout mice. Altogether, our results uncover a new role for Atg7 in the biogenesis of the acrosome, and we provide evidence to support the autolysosome origination hypothesis for the acrosome.

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Section: Discussionsupporting

confidence: 64%

Atg7 is required for acrosome biogenesis during spermatogenesis in mice

et al. 2014

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“…Interestingly, gigaxonin, like TBCE, localizes at the Golgi apparatus (Cullen et al, 2004). Wobbler mice, a model of progressive motor neuron degeneration, are mutated in VPS54 (vacuolar protein sorting 54), a protein of the Golgi-associated retrograde complex (Schmitt-John et al, 2005). In these mice, defective axonal transport (Mitsumoto and Gambetti, 1986) and progressive axonal degeneration (Mitsumoto and Bradley, 1982) are associated with downregulation of the tubulin chaperone TBCA and of ␣3-tubulin (Perrin et al, 2006).…”

Section: Retrograde Microtubule Loss In Pmn Micementioning

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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“…Some missense mutations in VCP cause inherited MND ) and motor neuron abnormalities are present in many patients with IBMPFD. Furthermore, a missense mutation in vacuolar protein sorting 54 (Vps54), the homolog of VCP, causes motor neuron degeneration in the wobbler mouse, a model of MND (Schmitt-John et al 2005). VCP belongs to the type II AAA þ (ATPases associated with a variety of activities) family and takes part in multiple cellular processes, including protein quality control, nuclear functions, and the regulation of membrane dynamics.…”

Section: Mutations In Vcpmentioning

confidence: 99%