Lack of GDAP1 Induces Neuronal Calcium and Mitochondrial Defects in a Knockout Mouse Model of Charcot-Marie-Tooth Neuropathy

27 páginas, 9 figuras.Mutations in GDAP1, which encodes protein located in the mitochondrial outer membrane, cause axonal recessive (AR-CMT2), axonal dominant (CMT2K) and demyelinating recessive (CMT4A) forms of Charcot-Marie-Tooth (CMT) neuropathy. Loss of function recessive mutations in GDAP1 are associated with decreased mitochondrial fission activity, while dominant mutations result in impairment of mitochondrial fusion with increased production of reactive oxygen species and susceptibility to apoptotic stimuli. GDAP1 silencing in vitro reduces Ca2+ inflow through store-operated Ca2+ entry (SOCE) upon mobilization of endoplasmic reticulum (ER) Ca2+, likely in association with an abnormal distribution of the mitochondrial network. To investigate the functional consequences of lack of GDAP1 in vivo, we generated a Gdap1 knockout mouse. The affected animals presented abnormal motor behavior starting at the age of 3 months. Electrophysiological and biochemical studies confirmed the axonal nature of the neuropathy whereas histopathological studies over time showed progressive loss of motor neurons (MNs) in the anterior horn of the spinal cord and defects in neuromuscular junctions. Analyses of cultured embryonic MNs and adult dorsal root ganglia neurons from affected animals demonstrated large and defective mitochondria, changes in the ER cisternae, reduced acetylation of cytoskeletal α-tubulin and increased autophagy vesicles. Importantly, MNs showed reduced cytosolic calcium and SOCE response. The development and characterization of the GDAP1 neuropathy mice model thus revealed that some of the pathophysiological changes present in axonal recessive form of the GDAP1-related CMT might be the consequence of changes in the mitochondrial network biology and mitochondria-endoplasmic reticulum interaction leading to abnormalities in calcium homeostasis.This work has been funded by grants from the Spanish Ministry of Economy and Competitiveness, grants no. SAF2009-07063 and SAF2012-32425 (to FP), the Collaborative Joint Project awarded by IRDiRC and funded by ISCIII grant IR11/TREAT-CMT, Instituto de Salud Carlos III (to both FP and JMC), the Generalitat Valenciana Prometeo Programme 2009/059 and 2014/029 (to FP) and the Swiss National Science Foundation, grant no. 31003A_135735/1 (to RC). This work has also been funded by the CIBERER, an initiative from the Instituto de Salud Carlos III. MB-M is the recipient of a FPI fellowship, from the Spanish Ministry of Economy and Competitiveness. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Hispano-Americans in Europe: what do we know about their health status and determinants? A scoping review.

BACKGROUND: Policy makers and health practitioners are in need of guidance to respond to the growing geographic mobility of Hispano-American migrants in Europe. Drawing from contributions from epidemiology, social sciences, demography, psychology, psychiatry and economy, this scoping review provides an up-to-date and comprehensive synthesis of studies addressing the health status and determinants of this population. We describe major research gaps and suggest specific avenues of further inquiry. METHODS: We identified systematically papers that addressed the concepts "health" and "Hispano Americans" indexed in five data bases from Jan 1990 to May 2014 with no language restrictions. We screened the 4,464 citations retrieved against exclusion criteria and classified 193 selected references in 12 thematic folders with the aid of the reference management software ENDNOTE X6. After reviewing the full text of all papers we extracted relevant data systematically into a table template to facilitate the synthesising process. RESULTS: Most studies focused on a particular disease, leaving unexplored the interlinkages between different health conditions and how these relate to legislative, health services, environmental, occupational, and other health determinants. We elucidated some consistent results but there were many heterogeneous findings and several popular beliefs were not fully supported by empirical evidence. Few studies adopted a trans-national perspective and many consisted of cross-sectional descriptions that considered "Hispano-Americans" as a homogeneous category, limiting our analysis. Our results are also constrained by the availability and varying quality of studies reviewed./nCONCLUSIONS:/nBurgeoning research has produced some consistent findings but there are huge gaps in knowledge. To prevent unhelpful generalisations we need a more holistic and nuanced understanding of how mobility, ethnicity, income, gender, legislative status, employment status, working conditions, neighbourhood characteristics and social status intersect with demographic variables and policy contexts to influence the health of the diverse Hispano-American populations present in Europe