Corinne Lautier

Mutations in the GIGYF2 (TNRC15) Gene at the PARK11 Locus in Familial Parkinson Disease

The genetic basis for association of the PARK11 region of chromosome 2 with familial Parkinson disease (PD) is unknown. This study examined the GIGYF2 (Grb10-Interacting GYF Protein-2) (TNRC15) gene, which contains the PARK11 microsatellite marker with the highest linkage score (D2S206, LOD 5.14). The 27 coding exons of the GIGYF2 gene were sequenced in 123 Italian and 126 French patients with familial PD, plus 131 Italian and 96 French controls. A total of seven different GIGYF2 missense mutations resulting in single amino acid substitutions were present in 12 unrelated PD index patients (4.8%) and not in controls. Three amino acid insertions or deletions were found in four other index patients and absent in controls. Specific exon sequencing showed that these ten sequence changes were absent from a further 91 controls. In four families with amino acid substitutions in which at least one other PD case was available, the GIGYF2 mutations (Asn56Ser, Thr112Ala, and Asp606Glu) segregated with PD. There were, however, two unaffected carriers in one family, suggesting age-dependent or incomplete penetrance. One index case (PD onset age 33) inherited a GIGYF2 mutation (Ile278Val) from her affected father (PD onset age 66) and a previously described PD-linked mutation in the LRRK2 gene (Ile1371Val) from her affected mother (PD onset age 61). The earlier onset and severe clinical course in the index patient suggest additive effects of the GIGYF2 and LRRK2 mutations. These data strongly support GIGYF2 as a PARK11 gene with a causal role in familial PD.

GIGYF2 Gene Disruption in Mice Results in Neurodegeneration and Altered Insulin-like Growth Factor Signaling

Grb10-Interacting GYF Protein 2 (GIGYF2) was initially identified through its interaction with Grb10, an adapter protein that binds activated IGF-I and insulin receptors. The GIGYF2 gene maps to human chromosome 2q37 within a region linked to familial Parkinsons disease (PARK11 locus), and association of GIGYF2 mutations with Parkinsons disease has been described in some but not other recent publications. This study investigated the consequences of Gigyf2 gene disruption in mice. Gigyf2 null mice undergo apparently normal embryonic development, but fail to feed and die within the first 2 post-natal days. Heterozygous Gigyf2(+/-) mice survive to adulthood with no evident metabolic or growth defects. At 12-15 months of age, the Gigyf2(+/-) mice begin to exhibit motor dysfunction manifested as decreased balance time on a rotating horizontal rod. This is associated with histopathological evidence of neurodegeneration and rare intracytoplasmic Lewy body-like inclusions in spinal anterior horn motor neurons. There are alpha-synuclein positive neuritic plaques in the brainstem and cerebellum, but no abnormalities in the substantia nigra. Primary cultured embryo fibroblasts from Gigyf2 null mice exhibit decreased IGF-I-stimulated IGF-I receptor tyrosine phosphorylation and augmented ERK1/2 phosphorylation. These data provide further evidence for an important role of GIGYF2 in age-related neurodegeneration and IGF pathway signaling.

Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases

Animal models are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates. Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher. Despite these caveats, considerable scientific advances have been possible using nonhuman primates. This review concisely summarizes their role in the study of aging and of the mechanisms involved in neurodegenerative disorders associated mainly with cognitive dysfunctions (Alzheimers and prion diseases) or motor deficits (Parkinsons and related diseases).

Association of the FTO gene with obesity and the metabolic syndrome is independent of the IRS-2 gene in the female population of Southern France.

AIM The objective of the present study was to investigate the genetic association of the fat-mass-and-obesity-associated (FTO) gene in obese women in the presence of the known influential role of the insulin receptor substrate 2 (IRS-2) gene. METHODS This case-control study was carried out in the Languedoc-Roussillon region of France, and included lean control women (n=128), and women (n=119) of various degrees of obesity (body mass index [BMI] mean+/-S.D.: 39.3+/-7.4kg/m(2)) and a prevalence of 26.9% of the metabolic syndrome (MetS). For the FTO gene, genotyping was performed by sequence-specific oligonucleotide-polymerase chain reaction (SSO-PCR) on the single nucleotide polymorphism (SNP) rs1421085 (C/T) while, for IRS-2, the rs1805097 (G/A) corresponding to variant Gly1057Asp was genotyped by direct sequencing. RESULTS The FTO gene (homozygous C/C) was significantly associated to both simple and morbid obesity (P<0.026 and P<0.0034, respectively), with odds-ratios (ORs) of 2.58 (95% CI: 1.1-6.0) and 4.1 (95% CI: 1.6-10.5), respectively, independent of IRS-2. MetS was also associated with FTO (P<0.032, OR: 3.1, 95% CI: 1.1-8.5), but not with IRS-2. Genotypes of FTO were correlated with insulin resistance, and homozygous C/C was positively correlated with an increase in insulin resistance over the value predicted by the increase in BMI. CONCLUSION These data confirm the influential role of the FTO gene in obesity in the French female population and, in addition, revealed the role of FTO in insulin resistance and MetS. These effects appeared to be independent of IRS-2, which is directly involved in insulin action. This study may offer new insights into the genetic determinants of obesity and MetS in women.

Branched-Chain Amino Acid Database Integrated in MEDIPAD Software as a Tool for Nutritional Investigation of Mediterranean Populations

Branched-chained amino acids (BCAA) are essential dietary components for humans and can act as potential biomarkers for diabetes development. To efficiently estimate dietary intake, we developed a BCAA database for 1331 food items found in the French Centre d’Information sur la Qualité des Aliments (CIQUAL) food table by compiling BCAA content from international tables, published measurements, or by food similarity as well as by calculating 267 items from Greek, Turkish, Romanian, and Moroccan mixed dishes. The database embedded in MEDIPAD software capable of registering 24 h of dietary recalls (24HDR) with clinical and genetic data was evaluated based on archived 24HDR of the Saint Pierre Institute (France) from 2957 subjects, which indicated a BCAA content up to 4.2 g/100 g of food and differences among normal weight and obese subjects across BCAA quartiles. We also evaluated the database of 119 interviews of Romanians, Turkish and Albanians in Greece (27–65 years) during the MEDIGENE program, which indicated mean BCAA intake of 13.84 and 12.91 g/day in males and females, respectively, comparable to other studies. The MEDIPAD is user-friendly, multilingual, and secure software and with the BCAA database is suitable for conducting nutritional assessment in the Mediterranean area with particular facilities for food administration.

Old Gray Mouse Lemur Behavior, Cognition, and Neuropathology

Abstract Nonhuman primate models are required to understand aging and age-related pathologies. The gray mouse lemur Microcebus murinus, a small prosimian primate, develops age-dependent deficits that are comparable to the decline observed during normal and pathological aging in humans. Importantly, not all old gray mouse lemurs are equally affected by age-related behavioral and cognitive problems. Some are profoundly impaired, while others perform as well as younger animals. Moreover, brain atrophy is detected only in some animals and thus appears to be an age-related pathological condition more than an inevitable effect of age. Finally, a subset of aged animals display neuropathological lesions observed also in Alzheimers disease: β-amyloid deposition mainly in diffuse plaques and tau protein aggregation in some pyramidal neurons of the entorhinal cortex and hippocampus. Overall, these age-related changes indicate that gray mouse lemurs could be used as a potential translational model to study age-associated deficits and disorders.