Dataset Information

Secreted VAPB/ALS8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors.

ABSTRACT: The VAPB/ALS8 major sperm protein domain (vMSP) is implicated in amyotrophic lateral sclerosis and spinal muscular atrophy, yet its function in the nervous system is not well understood. In Caenorhabditis elegans and Drosophila, the vMSP is cleaved from its transmembrane anchor and secreted in a cell type-specific fashion. We show that vMSPs secreted by neurons act on Lar-like protein-tyrosine phosphatase and Roundabout growth cone guidance receptors expressed in striated muscle. This signaling pathway promotes Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich muscle I-bands. C. elegans VAPB mutants have mitochondrial localization, morphology, mobility, and fission/fusion defects that are suppressed by Lar-like receptor or Arp2/3 inactivation. Hence, growth cone guidance receptor pathways that remodel the actin cytoskeleton have unanticipated effects on mitochondrial dynamics. We propose that neurons secrete vMSPs to promote striated muscle energy production and metabolism, in part through the regulation of mitochondrial localization and function.

SUBMITTER: Han SM

PROVIDER: S-EPMC3298687 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Secreted VAPB/ALS8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors.

Han Sung Min SM Tsuda Hiroshi H Yang Youfeng Y Vibbert Jack J Cottee Pauline P Lee Se-Jin SJ Winek Jessica J Haueter Claire C Bellen Hugo J HJ Miller Michael A MA

Developmental cell 20120119 2

<h4>Video abstract</h4>The VAPB/ALS8 major sperm protein domain (vMSP) is implicated in amyotrophic lateral sclerosis and spinal muscular atrophy, yet its function in the nervous system is not well understood. In Caenorhabditis elegans and Drosophila, the vMSP is cleaved from its transmembrane anchor and secreted in a cell type-specific fashion. We show that vMSPs secreted by neurons act on Lar-like protein-tyrosine phosphatase and Roundabout growth cone guidance receptors expressed in striated ...[more]

PMID: 22264801

Similar Datasets

Project description:Amyotrophic lateral sclerosis 8 (ALS8) is a predominantly lower motor neuron syndrome originally described in a Portuguese-Brazilian family, which originated from a common founder. ALS8 is caused by a VAPB mutation and extremely rare in Central Europe. We present a 51-year-old German man with ALS8 who had the P56S VAPB mutation independently of the founder effect. In the final 4 years of his life (disease duration 10 years), the patient had five MRI scans and four in-depth neuropsychological assessments. This paper addresses the course of the patient's cognitive status and relates cognitive performance to structural brain changes in order to determine whether this ALS8 case showed a different pattern of cognitive decline compared with sporadic ALS. The executive functions, verbal fluency, and memory of the patient and 17 age-, sex-, and education-matched controls were assessed on four different occasions. His cognitive performance and decline were investigated for abnormality using cross-sectional and longitudinal matched case-control analysis. We obtained five T1-weighted MRI, which we analyzed using voxel-wise non-parametric analysis with statistical non-parametric mapping in Matlab. Moreover, we conducted a single-subject correlation between cognitive performance and brain atrophy. The cognitive profile of the index patient featured executive dysfunction. Notably, his working memory and shifting ability declined from a healthy baseline to an impaired performance, leading to a transition from cognitively non-impaired (ALSni) to cognitively impaired (ALSci). The correlations we observed between cerebellar atrophy and verbal fluency in addition to fusiform gyrus atrophy and shifting are novel findings. We found that the conversion from ALSni to ALSci was associated with widespread cerebral atrophy, which extended beyond the primary motor and premotor cortex and affected, among others, the cerebellum and left fusiform gyrus. The index patients' cognitive profile resembles that of other ALS phenotypes, but the extensive atrophy beyond extra-motor areas has not yet been described.

Project description:BackgroundFAF1 is a ubiquitin-binding adaptor for the p97 ATPase and belongs to the UBA-UBX family of p97 cofactors. p97 converts the energy derived from ATP hydrolysis into conformational changes of the p97 hexamer, which allows the dissociation of its targets from cellular structures or from larger protein complexes to facilitate their ubiquitin-dependent degradation. VAPB and the related protein VAPA form homo- and heterodimers that are anchored in the endoplasmic reticulum membrane and can interact with protein partners carrying a FFAT motif. Mutations in either VAPB or p97 can cause amyotrophic lateral sclerosis, a neurodegenerative disorder that affects upper and lower motor neurons.ResultsWe show that FAF1 contains a non-canonical FFAT motif that allows it to interact directly with the MSP domain of VAPB and, thereby, to mediate VAPB interaction with p97. This finding establishes a link between two proteins that can cause amyotrophic lateral sclerosis when mutated, VAPB/ALS8 and p97/ALS14. Subsequently, we identified a similar FFAT-like motif in the ASNA1 subunit of the transmembrane-domain recognition complex (TRC), which in turn mediates ASNA1 interaction with the MSP domain of VAPB. Proteasome inhibition leads to the accumulation of ubiquitinated species in VAPB immunoprecipitates and this correlates with an increase in FAF1 and p97 binding. We found that VAPB interaction with ubiquitinated proteins is strongly reduced in cells treated with FAF1 siRNA. Our efforts to determine the identity of the ubiquitinated targets common to VAPB and FAF1 led to the identification of RPN2, a subunit of an oligosaccharyl-transferase located at the endoplasmic reticulum, which may be regulated by ubiquitin-mediated degradation.ConclusionsThe FFAT-like motifs we identified in FAF1 and ASNA1 demonstrate that sequences containing a single phenylalanine residue with the consensus (D/E)(D/E)FEDAx(D/E) are also proficient to mediate interaction with VAPB. Our findings indicate that the repertoire of VAPB interactors is more diverse than previously anticipated and link VAPB to the function of ATPase complexes such as p97/FAF1 and ASNA1/TRC.

Project description:Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Examining the muscle biopsy of our index ALS8 patient of European origin revealed globular accumulations of VAPB aggregates co-localised with autophagy markers LC3 and p62 in partially atrophic and atrophic muscle fibres. In line with this skin fibroblasts obtained from the same patient showed accumulation of P56S-VAPB aggregates together with LC3 and p62. Detailed investigations of autophagic flux in cell culture models revealed that P56S-VAPB alters both initial and late steps of the autophagy pathway. Accordingly, electron microscopy complemented with live cell imaging highlighted the impaired fusion of accumulated autophagosomes with lysosomes in cells expressing P56S-VAPB. Consistent with these observations, neuropathological studies of brain and spinal cord of P56S-VAPB transgenic mice revealed signs of neurodegeneration associated with altered protein quality control and defective autophagy. Autophagy and RBP homeostasis are interdependent, as demonstrated by the cytoplasmic mis-localisation of several RBPs including pTDP-43, FUS, Matrin 3 which often sequestered with P56S-VAPB aggregates both in cell culture and in the muscle biopsy of the ALS8 patient. Further confirming the notion that aggregation of the RBPs proceeds through the stress granule (SG) pathway, we found persistent G3BP- and TIAR1-positive SGs in P56S-VAPB expressing cells as well as in the ALS8 patient muscle biopsy. We conclude that P56S-VAPB-ALS8 involves a cohesive pathomechanism of aberrant RBP homeostasis together with dysfunctional autophagy.

Project description:BackgroundThe pathogenesis of teratozoospermia (<4% morphologically normal sperm cells) and the relationship between sperm morphological abnormalities and abnormal sperm nuclear DNA fragmentation, which are considered indicators of male fertility, have not been elucidated. Our research was designed to determine the prevalence of different sperm DNA fragmentation (SDF) levels in men with teratozoospermia and to establish a discriminating threshold value for SDF in assessing sperm morphology.MethodsBasic semen characteristics and detailed sperm morphological analysis (head, neck, midpiece, and tail defects and excess residual cytoplasm) (WHO, 2010), and the nuclear sperm DNA dispersion test were performed on semen samples obtained from 523 men with teratozoospermia (n=296) and those without teratozoospermia (n=227).ResultsSubjects with abnormal sperm morphology had not only lower results for standard sperm characteristics, including detailed sperm morphological abnormalities, but also a higher proportion of sperm cells with SDF vs. men with normal sperm morphology. Moreover, significantly fewer subjects with low SDF levels (≤15%), more subjects with high SDF levels (>30%) and a higher odds ratio (OR) for having high SDF levels were found in the group of men with teratozoospermia vs. men without teratozoospermia. However, the receiving operating characteristic (ROC) curve analysis indicated that a SDF >18% was a significant negative predictive value to distinguish between men with normal sperm morphology or men with abnormal sperm morphology. The optimal area under the ROC curve (AUC) was 0.746. In the group of men with teratozoospermia, a higher incidence of men with >18% SDF and a higher OR for having >18% SDF were observed. SDF negatively correlated with sperm number, morphologically normal sperm cells, sperm motility and sperm vitality but positively correlated with the teratozoospermia index (TZI) and detailed sperm morphological abnormalities.ConclusionsThe obtained findings demonstrated that: (I) detailed sperm structural defects coexist with abnormal nuclear sperm DNA dispersion, (II) men with teratozoospermia may have a higher risk for sperm DNA damage, (III) the calculated optimal SDF value of 18% measured by the DNA sperm dispersion test is the best criterion to predict normal and abnormal sperm morphology.

Dataset Information

Secreted VAPB/ALS8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors.

Publications

Secreted VAPB/ALS8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets