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    IBRO Alumni Symposium at 2nd FALAN Congress

    The IBRO Alumni Committee under the leadership of its Chair, Valeria della Maggiore (Universidad de Buenos Aires, Argentina), will hold an IBRO Alumni Symposium at the next Federation of Latin American and Caribbean Neuroscience Societies (FALAN) Congress in Buenos Aires, Argentina, on 18 October 2016. Five IBRO alumni - Lionel Muller Igaz, Helena Cimarosti, Elena Avale, Glaucia N.M. Hajj and Tomas Falzone - have been selected to share their research on basic and translational research in neurodegenerative diseases. To find out more, you can read their abstracts below. All are welcome to attend!

    IBRO ALUMNI SYMPOSIUM AT FALAN

    FALAN Symposium 7

    Basic and Translation Research in Neurodegenerative Disease: From Molecules to Animal Models
    Tuesday, 18 October 2016, from 11:00 - 13:00 – Room 1, Golden Center, Buenos Aires, Argentina
    Chair: V. Della Maggiore 

    This symposium reunites five IBRO alumni speakers that specialize in the pathophysiology of neurodegenerative disorders including Alzheimer’s, Parkinson’s and Prion diseases. The talks will discuss state-of- the-art work based on structural and molecular biology, neurogenetics, cellular and transgenic mouse models aimed at elucidating the etiology of these disorders and devising potential therapeutic strategies.

    PROGRAM

    Conditional mouse models of TDP-43 proteinopathies
    Lionel Muller Igaz

    IFIBIO Houssay (CONICET), School of Medicine, University of Buenos Aires, Argentina

    TDP-43 mislocalization and aggregation are hallmark features of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). We have previously shown in mice that inducible overexpression of a cytoplasmically-localized form of TDP-43 (TDP-43-ΔNLS) in forebrain neurons evokes neuropathological changes that recapitulate several features of TDP-43 proteinopathies. Detailed behavioral phenotyping could provide further validation for its usage as a model for FTD. In the present study, we performed a battery of behavioral tests to evaluate motor, cognitive and social phenotypes in this model. We found that transgene (Tg) induction by doxycycline (dox) removal at weaning led to motor abnormalities including hyperlocomotion in the open field test, impaired coordination and balance in the rotarod test and increased spasticity as shown by a clasping phenotype. Cognitive assessment demonstrated impaired recognition and spatial memory, measured by novel object recognition and Y-maze tests. Remarkably, TDP-43-ΔNLS mice displayed deficits in social behavior, mimicking a key aspect of FTD. In order to analyze if these symptoms were reversible, we suppressed Tg expression for 14 d in young mice, which showed an established behavioral phenotype but modest neurodegeneration, and found that motor and cognitive deficits were ameliorated; however, social performance remained altered. When older mice (exhibiting overt neurodegeneration) were suppressed with dox, the motoric phenotypes were not reversible. These results indicate that TDP-43-ΔNLS mice display several core behavioral features of FTD with motor neuron disease, possibly due to functional changes in the surviving neurons, and might serve as a valuable tool to unveil the underlying mechanisms of this and other TDP-43 proteinopathies.

    Protein SUMOylation in Alzheimer’s disease
    Helena Cimarosti
    Department of Pharmacology, Federal University of Santa Catarina, Brazil

    Alzheimer’s disease (AD) is the most common cause of chronic dementia among the elderly, with an estimated ~40 million patients diagnosed worldwide, a number predicted to almost double every 20 years. Therefore, the mechanisms underlying neuronal death in AD are the focus of intense research. SUMOylation acts as a biochemical switch in many pathways, regulating the function of several proteins, and is thus crucial in all eukaryotic cells. It has emerged recently that SUMOylation is involved in neuronal signalling cascades and is implicated in many neurodegenerative diseases, including AD. We are currently investigating the effects of manipulating SUMOylation and deSUMOylation pathways in cultured neurons and animal models of AD. In particular, we are focusing on the role of potential SUMO targets relevant to mitochondrial dysfunction and neuronal death, e.g. dynamin-related protein 1 and voltage-gated calcium channels. This work will reveal if SUMOylation represents a potentially tractable target for therapeutic intervention and may also identify novel SUMO substrates for drug development.

    Phenotypic rescue in a mouse model of tauopathy using trans-splicing RNA reprogramming
    Elena Avale

    Laboratory of Experimental therapeutics in neurodegenerative processes, INGEBI (CONICET), Buenos Aires, Argentina

    Tauopathies are neurodegenerative diseases characterized by the presence of intraneuronal aggregates of the protein tau in insoluble neurofibrillary tangles (NFTs). Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in microtubule polymerization and axonal transport. Alternative splicing of exon 10 (E10) in the Tau transcript produces protein isoforms with three (3R) or four (4R) microtubule binding repeats, which are expressed in equal amounts in the normal adult human brain. Several tauopathies, are associated with mutations affecting exon 10 alternative splicing, leading to an imbalance between 3R and 4R isoforms. Correction of that imbalance represent a therapeutical approach for those tauopathies.

    In this talk, I will summarize our achievements using RNA reprogramming to modulate Tau 4R/3R ratio in vivo. We characterized a mouse model of tauopathy which displays an excess of Tau 3R, evidencing cognitive impairment and the presence of NFTs and neurodegeneration in cortical areas from 9 months old. We restored the Tau 3R/4R balance inducing a trans- splicing reaction between the endogenous Tau transcript and exogenous RNA pre-trans- splicing molecule (PTM), locally delivered in the prefrontal cortex by lentiviral vectors. Rescued mice displayed normal performance in cognitive tests and a reduction of hyphosphorylated Tau in the injected areas. Our results provide evidence that Tau RNA reprogramming might be a plausible strategy for treating human tauopathies related to tau mis-splicing. 

    Cellular Prion is a resistance factor for the development of type 2 diabetes
    Glaucia N.M. Hajj

    International Research Center, AC Camargo Cancer Center, São Paulo, Brazil

    Type 2 diabetes, the most common form of the disease, has become one of the major public health problems currently known. The cellular prion protein (PrPC) is a cell surface molecule identified due to its relationship with prion diseases, fatal progressive neurodegenerative diseases. In this work, we describe that animals knockout for cellular prion protein (PrPC KO) present all the symptoms associated to the development of type 2 diabetes: hyperglycemia, hyperinsulinemia and obesity upon a high fat diet. Conversely, animals that overexpress PrPC (TG20) have an increased resistance to develop type 2 diabetes on a high fat diet. Cellular models reproduce the phenotype, with the PrPC KO cells presenting reduced glucose uptake in response to insulin and TG20 cells with an increased glucose uptake. Cell models of prion diseases also show a reduction in glucose uptake, suggesting that glucose intolerance may be one of the prion diseases symptoms. The mechanism to explain these alterations rely on the altered translocation of the glucose transporter Glut4. Thus, our results indicate that PrPc could be a susceptibility factor for the development of type 2 diabetes and metabolic syndrome.

    Novel α-Synunclein mediates the pathogenic mutation-dependent mitochondrial dysfunction in Parkinson’s Disease
    Tomas Falzone

    IBCN (CONICET), School of Medicine, University of Buenos Aires; IBYME-CONICET, Buenos Aires, Argentina

    Parkinson’s Disease (PD), the second most prevalent neurodegenerative disorder, is characterized pathologically by a progressive loss of neurons and the accumulation of eosinophilic intracellular inclusions, termed Lewy bodies. The mayor component of these inclusions is α-synuclein (α-Syn), the first protein identified with dominant inheritance in familial PD (fPD). Later, a number of genes contributing to fPD have been identified from which Pink1, Parkin, DJ-1 and recently VPS35 have a direct role in controlling mitochondria, suggesting a mayor role of this pathway in disease progression. Although genetic mutations identified so far account for a small proportion of PD cases; there are pathological, pharmacological and genetic evidences supporting a common sporadic form of the disease (sPD) involving defects in neuronal mitochondrial homeostasis. Recently much attention has been dedicated to the possible role α-Syn has on mitochondrial pathologies, although, the mechanism by which α-Syn impairs mitochondrial function remains unknown. To test the role of α-Syn in mitochondrial morphology and PD associated pathologies we generated human models with α-Syn overexpression to study the axonal mitochondrial transport and morphology in human derived neurons from hESC or modified hiPSC. Stem cells are extremely promising for future cell replacement therapies, however, much need to be understood on the mechanisms leading into neurodegenerative diseases such as PD.

    Genome editing of induced pluripotent stem cells opens a new path in the study of human pathologies. We provide novel evidence of a differential effect of α-Syn mutations in a common pathological pathway involving the control of mitochondrial fragmentation in human neurons. Moreover, by genome edition we uncover a new physiological role for α-Syn in the neuronal maintenance of mitochondrial size and distribution in axons. This knowledge provides an important contribution to the role that α-Syn could induce in the early neuropathology associated with the mitochondria in PD and highlight a potential novel therapeutic strategy for early intervention in PD, prior to neuronal loss and clinical manifestation of disease.