Follow the news on the SPATAX/ASG meeting on spastic paraparesis and ataxias

5th International Meeting on Spastic Paraparesis and Ataxias

Local organizers: Alexandra Durr, MD–PhD (APHP, UPMC) / Giovanni Stevanin, PhD (INSERM, EPHE)
European organizers: Holm Graessner, PhD (University of Tuebingen)
Sessions co-organizers: Sylvia Boesch, Thomas Klockgether, Caterina Mariotti, Massimo Pandolfo, Evan Reid, Olaf Riess, Ludger Schöls, Chantal Tallaksen, Enza Maria Valente, Bart Van de Warrenburg

Local staff: Sandra Benaich, Elodie Petit and Tiffany Monnier

Members of the Ataxia Study Group (ASG), of the SPATAX Network as well as researchers from all over the world met at the Brain and Spine Institute, in Paris, during 3 days. The program included 14 plenary lectures from leaders in the field of spinocerebellar diseases (dominant and recessive forms of cerebellar ataxias and spastic paraplegias), 27 short talks and 2 poster sessions. Five satellite meetings were also organised as opportunities of exchanges on these rare disorders. In total 230 researchers gathered in Paris during these 3 days from all 5 continents (22 countries).

Full Programme with Abstracts (English): Booklet 2016

Résumé et programme complet (Français): Conférences-Français-2016

FOLLOW US on: https://www.facebook.com/SPATAX-186083254777101/

Photos: Julien Branchu, Marie Coutelier, Antoine Bonvoisin, Giovanni Stevanin

Sponsors:sponsors

 

22/06/2016

The staff and the Spatax team are ready to welcome you tomorrow for the 5th international meeting on ataxias and spastic paraplegias at ICM – Institut du Cerveau et de la Moelle épinière, Paris

Nous sommes prêt pour vous accueillir demain au congrès sur les ataxies et les paraplégies spastiques!!!

Merci à Sandra Benaich, Elodie Petit and Tiffany Monnier for the organization

 

22/06/2016

First satellite meeting of the Spatax/ASG conference, PREPARE Erare (coordination: M Synofzik), started this evening at Bercy village Chai33 restaurant. The main topic was SHARING experience in recessive ataxias in a nice atmosphere with specialists from Strasbourg, Montpellier, Montreal, Saguenay, Antwerpen, London, Tuebingen and Paris. Tomorrow the discussions on the way we will share the data and experiences will continue!!

 

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23/06/2016

First Day of the SPATAX/ASG meeting dedicated to functional studies. We are gathering 230 people today from 22 countries from all 5 continents…

…in presence of representatives of 6 patients associations, including EURO-HSP, TWS, CSC, ASL, AFAF…

 

  • Introduction by Alexandra Durr, Giovanni Stevanin and Henry Wahlig
  • 20 years of research  on Spinocerebellar ataxia 1 were summarized by Harry Orr, a good example of how deciphering the mechanisms can bring important information for future therapy focusing on cck/cckR1 targeting

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  • Martina Marinello told us how the SUMOylation pathway is downregulated in the cerebellum of SCA7 mice probably leading to less degradation of the pathological protein, a nice and unique example of degradation defect in the nucleus leading to neurodegeneration

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  • Teisha Bradshaw showed us that loss of function of sacsin (involved in ARSACS) lead to an abnormal mitochondrial network, reduced mitochondrial gene expression, increased oxydative stress with increased ROS and loss of DRP1 localisation to mitochondria probably impairing the fission process of this network

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  • Tripathy Debasmita showed us that mutant forms of TGM6/SCA35 are associated with increased unfolded protein response

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  • A slight increase of anterograde velocity of VAMP7-containing vesicles was noted by Andrea Burgo in cortical neurons of SPG4 KO mice with a change in the balance towards more anterograde transport of mitochondria as a consequence of less severing microtubule activity

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  • Christelle Durand demonstrated how it is important to develop functional tests to validate missense mutations. This was illustrated on SPG56/CYP2U1

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  • The talk of Harald Stenmark was dealing on function of spastin that is recruited by IST1 to microtubules to generate the nuclear envelope during anaphase. He also showed that protrudin-positive ER colocalizes with late endosomes; the KO of protrudin leads to the accumulation of perinuclear late endosomes while overexpression leads to the formation of protrusions accumulating late endosomes far from the nucleus
  • Elena Rugarli focused her talk on lipid droplets that colocalise with M1-SPAST, and that are increased in number in SPAST KO,  with a remodeling of lipid content in their cells (reduced cholesterol, increase phospholipids levels…). Spastin probably moves to LD when they are formed from ER

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  • Julien Branchu showed us that the KO of SPG11, the most frequent mutated AR-HSP gene, mimics very well the phenotype of SPG11 patients and that neurons accumulate aggregates connected to lysosomes containing proteins and lipids and very lately P62, indicating that autophagy mediated by the later is a late event in the pathology while lysosomal dysfunction is an early event

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  • Cecilia Mancini modeled the SCA28 pathology by a KI strategy with the p.M665R mutation. She showed that this mutation has a dominant negative effect with impaired mitochondrial dynamics

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  • This session was followed by a cocktail in front of posters to promote discussions

 

24/06/2016

Second day of the SPATAX/ASG meeting dedicated to clinico-genetics and therapeutics.

Peter Bauer showed us the improvements and the limits of genetic diagnosis in spastic paraplegias and ataxias and pinpointed the problems of incidental findings. Working on 5800 mendelian disorders would require 25000 experts to allow proper iterpretation of variants making this a challenge for future improvements in bioinformatics and methods. Panels give yield of only 25% in ataxias and 40% in HSP

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Tzoulis Charalampos gave an overview of mitochondrial involvement in ataxias

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Enza Maria Valente (for Roberta de Mori) presented for the first time SUFU mutations in congenital cerebellar malformations

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The CANVAS syndrome was then described by Richard Roxburgh as a Frieidreich-like clinical entity

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Claire Guissart studied a patient with a homozygous p.R26G mutation. Despite that this mutation was associated to decreased levels of frataxin, lipid accumulations and abnormal mitochondria in KI mice, it was found to not be the main cause of the disease in the patients since not segregating with the disease and since exome sequencing reported a mutation in Triple A syndrome gene, also fitting with the clinical presentation. This points the fact that segregation analysis is one of the key features to declare a mutation as causative and that functional studies may not be the gold standard for mutation validation

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Valeria Tiranti gave an overview of Neuronal Brain Iron Accumulation, a phenotype overlapping with HSP and ataxia. Causative genes are related to mitochondrial functions, iron metabolism and other functions (fatty acid metabolism, autophagy, lisosomal activity). Interestingly PLA2G6 and PANK2 KO mice do not have brain iron accumulations

Then Rebecca Schule showed us how the analysis of large series of patients with spastic paraplegia but pinpointed that there is very limited explanation on the variability in age at onset and severity. The lack of biomarkers is also an issue for future therapeutics except in SPG5

Matthis Synofzik pointed that mutations in SYNE1 are frequent (5-6%) and are not restricted to Quebec. They account for a large range of phenotypes from pure cerebellar ataxia to multisystemic ataxia with motor neuron disease

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Evaluation scales are not adequate for early onset and late onset patients according to a study presented by Audrey Tanguy

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Ilaria Giordano reported a cohort of 249 sporadic cases and showed that some converted to Multiple System Atrophy that progresses more rapidly  than spinocerebellar ataxias (inherited or not)

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Frataxine is involved in iron homeostasis, oxydative stress and Fe-S biosynthesis. Hélène Puccio presented an overview of our knowledge towards therapy

Beverly Davidson is working on the silencing of SCA1 as a therapeutic option.  She showed a dose-dependent preventive effect of motor deficits in SCA1 mice by injection of AAV overexpressing antisenses in the cerebellum at 5 weeks. Treatment at 11 weeks does not completely restores the wild type phenotype

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Ivelisse Sanchez highlighted mitochondrial dysfunctions in SCA1 cerebellum in mice with altered ATP levels but also dysregulation of the GSK3B/mTOR pathway at early stages of the disease

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Eleonora Di Gregorio talked about one of the main SCA38 mutation, p.Gly230Val, and showed that it was not altering the enzymatic function of ELOVL5 but modifies the localisation of the protein to Golgi instead of ER. Chemical chaperones relocated the protein to ER and might be an interesting therapeutic option

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Jonas Alex Morales Saute showed an increased oxydative stress in SCA3 serum of patients, supposed to increase the nuclear localisation of the pathological protein. Lithium treatment normalized ROS levels in patients and placebo as well however

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Thorsten Schmidt is using a screening approach in c.elegans to find molecules that allow to maintain the ataxin 3 in the cytoplasm and then reduce its aggregate formation and toxicity. This strategy is based on the fact that the localisation of ataxin 3 in the nucleus is dependent on KPNA3 and that its KO or knock down rescues SCA3 phenotype in various models

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Benjamin Cravatt has developed screening methods of inhibitors of enzymes based on competition with labeled probes targeting their active site. This would be usefull for the increasing number of ataxias or spastic paraplegias in which enzymes of the metabolism are implicated

Fanny Mochel has explored metabolic abnormalities in patients with dominant ataxias. Lower FA (by DTA), NAA and Glu (by spectroscopy profiling) worsen with disease duration in SCAs. But is this enough for monitoring clinical trials?

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The scientific meeting of the second day ended by two lectures on spinocerebellar ataxia SCA14 by Martina Minnerop and Anne Grosch. This clinico-genetic entity accounts for a relatively pure cerebellar ataxia with mild progression, with myoclonus and dystonia that may result from cerebellar desinhibition, and pure cerebellar atrophy at MRI associated with decreased NAA/Cr levels limited to the vermis

The gala dinner closed this second day:

25/06/2016

Third and last day of the SPATAX/ASG meeting dedicated mainly to diagnosis (and HSP functional studies).

Dineke Verbeek gave us an overview on channel dysfunctions in ataxias, focusing on mutations affecting Kv4.3 (SCA19/22). Her team has shown that its trafficking from the ER to plasma membrane is mediated by Kchip2. The mutant forms of Kv4.3 accumulate in Purkinje cells. In vitro the stability of the wild type protein (Kv4.3 forms tetrameres) is also aletered by the mutant form but the complex stability can be rescued by Kchip2 overexpression

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The spastin protein is involved in ER morphogenesis and also endosomal tubule fission processes which are both affected in spastic paraplegias. A third main pathway altered in these diseases is also lysosomal dysfunction and Evan Reid showed us how these 3 main pathways are interconnected and involve spastin: spastin lack led to many downstream effects in addition to ER and endosomal defects, including lysosomal abnormal morphology that can be rescued by M1 but also M87-spastin isoforms. The same applies on REEP1 mouse KO

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Timothy Newton (WINNER of the best oral presentation) reported a large SPG4 deletion also involving another gene, DPY30, with additional effects on lysosome size in cells

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Cahir O’Kane remember us that axons also contain ER wich is important for axon maintainance, lipid signalling and migth explain why long axons are mainly altered in spastic paraplegias

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Cyril Goizet reported a large series of patients from Europe with mutations in the SACS gene associated with abnormal mitochonrial functions and network

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Stefania Magri (WINNER of the best student presentation) and Sara Morais, talking about screening methods for diagnosis, highlighted the overlap between ataxias and spastic paraplegias and the need to analyse patients for all genes regardless of the mode of transmission

 

Non progressive congenital ataxias were studied by Lydie Burglen for mutations in a panel of genes covering early onset ataxias and some slowly progressive ataxias. The take-home message was the high frequency of de novo cases in early onset patients (60%), even in genes usually affecting progressive ataxias (SCA5, GRID2, SCA15…)

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Marie Coutelier reported a large candidate gene screening of 412 index cases of dominant ataxia , with two main causative genes involved: CACNA1A (4%) and SPG7 (2%), again illustrating the overlap between ataxias and spastic paraplegias. She also reported the first mutations in 3 families in CACNA1G, encoding a calcium channel that appears less sensitive and needs higher voltages for its function

 

Cecilia Marelli analysed 33 ataxia patients by an ataxia gene panel and a mini exome (4800 genes) and showed 42% of positive results, particularly in familal cases

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The SPATAX/ASG meeting ended with the awards based on the votes of all participants:

  • Best student oral presentation : 
    • S. Magri-A comprehensive NGS gene panel for the genetic diagnosis of spinocerebellar ataxias and spastic paraplegias: WINNER
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    • M. Coutelier-New generation sequencing approaches in autosomal dominant cerebellar ataxias: from panel cohort study to new gene identification
    • C. Mancini-Phenotype characterization of the SCA28 knock-in mouse model and derived embryonic fibroblasts

 

  • Best senior oral presentation
    • M. Newton-Epistatic effects influence SPG4 HSP age of onset: WINNER
    • DSCN0769
    • J. Branchu- SPG11 knockout in mouse mimics the pathology observed in patients
    • F. Mochel-Integrated multimodal biomarkers study in patients with SCA1, SCA2, SCA3 and SCA7

 

  • Best poster
    • N.Tadepalle-The role of Spastin in lipid droplet metabolism and its relevance to hereditary Spastic Paraplegia: WINNER
    • DSCN0771
    • Parodi-Exon analysis of 74 genes potentially involved in hereditary Spastic Paraplegias through targeted next generation sequencing
    • Schumacher-Functional analysis of the axonopathy related mutation N88S in seipin

 

25/06/2016

The end of the day was the occasion of specific meetings:

  • ALLIANCE (coordinator: R Schule)
  • ANR/FCT SPATAX-QUEST (coordinators: I. Alonso, G. Stevanin)
  • E-Rare PREPARE Ataxia (coordinator: M. Synofzik)

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  • E-rare Neurolipid (coordinator: E. Rugarli)

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See you next time…

 

 

 

 

 

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