Secreted VAPB/ALS8 Major Sperm Protein Domains Modulate Mitochondrial Localization and Morphology via Growth Cone Guidance Receptors

Han, Sung Min; Tsuda, Hiroshi; Yang, Youfeng; Vibbert, Jack; Cottee, Pauline; Lee, Se Jin; Winek, Jessica; Haueter, Claire; Bellen, Hugo J.; Miller, Michael A.

doi:10.1016/j.devcel.2011.12.009

Cited by 78 publications

(157 citation statements)

References 62 publications

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“…Treatment with mito-TEMPO does not result in the rescue of mitochondrial structural defects in the sel-12 mutants ( Figure S5C). To explore the consequence of having elevated ROS levels, we exposed sel-12 mutants to paraquat, an ROS generator that has been shown to cause toxicity dependent on endogenous ROS levels (Han et al 2012). We discovered that all three sel-12 mutants are hypersensitive to paraquat compared to wild-type animals ( Figure 7C).…”

Section: Mitochondrial Function 1461mentioning

confidence: 99%

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A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

Sarasija¹,

Norman

2015

Genetics

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Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) occur in most early onset familial Alzheimer's Disease. Despite the identification of the involvement of PSEN in Alzheimer's Disease (AD) 20 years ago, the underlying role of PSEN in AD is not fully understood. To gain insight into the biological function of PSEN, we investigated the role of the PSEN homolog SEL-12 in Caenorhabditis elegans. Using genetic, cell biological, and pharmacological approaches, we demonstrate that mutations in sel-12 result in defects in calcium homeostasis, leading to mitochondrial dysfunction. Moreover, consistent with mammalian PSEN, we provide evidence that SEL-12 has a critical role in mediating endoplasmic reticulum (ER) calcium release. Furthermore, we found that in SEL-12-deficient animals, calcium transfer from the ER to the mitochondria leads to fragmentation of the mitochondria and mitochondrial dysfunction. Additionally, we show that the impact that SEL-12 has on mitochondrial function is independent of its role in Notch signaling, g-secretase proteolytic activity, and amyloid plaques. Our results reveal a critical role for PSEN in mediating mitochondrial function by regulating calcium transfer from the ER to the mitochondria.KEYWORDS Caenorhabditis elegans; calcium; endoplasmic reticulum; mitochondria; presenilin M ITOCHONDRIA are highly dynamic organelles that are responsible for a myriad of functions including ATP production, generation and metabolism of reactive oxygen species (ROS), and apoptosis (Detmer and Chan 2007). Thus cells, in particular muscle cells and neurons due to their highenergy demands, are extremely reliant on mitochondrial function. Mitochondria also play a critical role in calcium homeostasis by acting as a calcium buffer. Calcium, in turn, regulates mitochondrial morphology, activity, and movement. The relevance of mitochondria is highlighted by the fact that many neurodegenerative diseases, such as Parkinson's and Alzheimer's Disease (AD) are characterized by abnormal mitochondrial activity and morphology (Cali et al. 2012).Mutations in the genes encoding presenilins (PSENs), PSEN1 and PSEN2, are the most common cause of early onset familial Alzheimer's Disease (FAD). PSENs are 50-kDa multipass transmembrane proteins that reside predominantly on the endoplasmic reticulum (ER) (Bezprozvanny and Mattson 2008) and have been shown to be enriched in an ER subcompartment that is in contact with mitochondria (Area-Gomez et al. 2009). Although altered PSEN function has been known to have a role in AD for 20 years (Sherrington et al. 1995), the functional consequences of mutations in PSENs are controversial and not understood. The prevailing model for the pathogenesis of AD is the "amyloid hypothesis," which states that an increase in b amyloid (Ab) 42 peptide is the major cause of neuronal degradation in AD (Hardy and Selkoe 2002); support for this hypothesis stems from the accumulation of amyloid plaques in the brains of AD patients (Hardy 2006). In addition to the "amyloid hypot...

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Section: Mitochondrial Function 1461mentioning

confidence: 99%

“…Sensitivity to paraquat (Aldrich) was analyzed as previously described (Han et al 2012). Briefly, 50 animals per strain were placed in tubes containing 100 ml of 0, 50, 100, or 150 mM paraquat in M9 buffer and incubated at 20°for 24 hr.…”

Section: Paraquat Assaymentioning

confidence: 99%

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

Sarasija¹,

Norman

2015

Genetics

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“…In this capacity, there is evidence for roles in lipid transport, Ca 2+ homeostasis, the unfolded protein response and other processes. VAPs also have a non-cellautonomous signaling function (Han et al, 2012(Han et al, , 2013Tsuda et al, 2008). In neurons and other cells, the MSPd is liberated from the transmembrane domain and unconventionally secreted into the extracellular environment.…”

Section: Introductionmentioning

confidence: 99%

“…The MSPd signals through Eph and Larlike receptors that modulate the actin cytoskeleton. An important MSPd target is striated muscle, where signaling regulates mitochondrial morphology and localization (Han et al, 2012(Han et al, , 2013.…”

Section: Introductionmentioning

confidence: 99%

The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1

Schultz¹,

Lee²,

Cole³

et al. 2017

Journal of Cell Science

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The major sperm protein domain (MSPd) has an extracellular signaling function implicated in amyotrophic lateral sclerosis. Secreted MSPds derived from the C. elegans VAPB homolog VPR-1 promote mitochondrial localization to actin-rich I-bands in body wall muscle. Here we show that the nervous system and germ line are key MSPd secretion tissues. MSPd signals are transduced through the CLR-1 Lar-like tyrosine phosphatase receptor. We show that CLR-1 is expressed throughout the muscle plasma membrane, where it is accessible to MSPd within the pseudocoelomic fluid. MSPd signaling is sufficient to remodel the muscle mitochondrial reticulum during adulthood. An RNAi suppressor screen identified survival of motor neuron 1 (SMN-1) as a downstream effector. SMN-1 acts in muscle, where it colocalizes at myofilaments with ARX-2, a component of the Arp2/3 actin-nucleation complex. Genetic studies suggest that SMN-1 promotes Arp2/3 activity important for localizing mitochondria to I-bands. Our results support the model that VAPB homologs are circulating hormones that pattern the striated muscle mitochondrial reticulum. This function is crucial in adults and requires SMN-1 in muscle, likely independent of its role in pre-mRNA splicing.

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“…Loss of UNC-6/Netrin resulted in a dramatic increase in the rate of neuronal cell death following muscle (Han et al, 2012). It is possible that, together or in parallel with the UNC-6/UNC-40 pathway, SAX-3 has a similar function in neurons.…”

Section: Discussion and Implications Of Findingsmentioning

confidence: 99%

The cellular and molecular mechanisms of axonal maintenance and regeneration

Coakley¹

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How a neuron responds to and withstands injury is a central question in neurobiology. Neuronal injury can be caused mechanically with force, chemically with toxic insults, or genetically with mutations in genes that lead to damage. The axon, the neuron's longest compartment, is often the focal point of degeneration due to traumatic injury, toxic insults, or neurodegenerative diseases.Damage to the axon can have drastic functional consequences for the organism. In some cases axonal injury can lead to death of the neuron, while in others repair mechanisms are triggered that promote regeneration of the injured axon. Important discoveries during the last decade have uncovered many components of the molecular machinery that regulate axonal degeneration and regeneration. However, the precise ways in which these pathways converge and respond to different insults remains largely unknown. Here, using the nematode Caenorhabditis elegans as an experimental model system, we present important discoveries outlining the cellular and molecular mechanisms underpinning axonal maintenance and regeneration. Using forward and reverse genetic approaches, combined with optogenetic, genetic, and laser-injury tools, we identify critical components of these biological processes. We demonstrate how genes functioning during axon development also have roles in mature axons, regulating both degeneration and regeneration.Firstly, we discover a role for MEC-7/β-tubulin in regulating both axon development and regeneration. Second, we develop and characterize an optogenetic method to induce cell ablation and neurodegeneration using the genetically encoded photosensitizer KillerRed. Third, we identify novel mutants with defects in axonal maintenance and describe a new phenomenon of neuronal fusion following genetically induced damage. Finally, we demonstrate a role for conserved components of the apoptotic machinery in the recognition of damaged neurons during regeneration.These findings both extend our understanding of the molecular mechanisms of axonal degeneration and regeneration, as well as provide new paradigms in which these processes can be investigated.

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Secreted VAPB/ALS8 Major Sperm Protein Domains Modulate Mitochondrial Localization and Morphology via Growth Cone Guidance Receptors

Cited by 78 publications

References 62 publications

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1

The cellular and molecular mechanisms of axonal maintenance and regeneration

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