AbstractsBiology & Animal Science

Heat shock proteins (HSPs) are attractive therapeutic targets for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), that are characterized by aberrant formation of protein aggregates. Small molecule HSP90 inhibitors are effective inducers of HSP gene expression in eukaryotic cells, including motor neurons, the primary cell type affected in ALS. Our lab has evaluated a novel small molecule HSP90 inhibitor, NXD30001, for in vitro efficacy using a primary culture model of fALS1 due to mutations in the SOD1 gene. Treatment with NXD30001 induced the expression of HSP40 and the inducible form of HSP70 (iHSP70) through activation of HSF1 and protected against several measures of mutant SOD1 (mSOD1) toxicity in primary motor neurons, including: protein aggregation and accumulation, mitochondrial fragmentation and motor neuron death. This study assessed NXD30001's ability to induce HSP gene expression in the SOD1G93A transgenic mouse model of ALS. Symptomatic SOD1G93A transgenic mice and nontransgenic wild-type mice were dosed intraperitoneally (i.p.) with NXD30001 and their tissues were analyzed for drug penetrance and expression of HSPs (HSP90, iHSP70, HSP60, HSP40 and HSP25). NXD30001 distributed to brain, spinal cord and peripheral tissues in SOD1G93A transgenic and nontransgenic mice after acute and subacute i.p. injections. The profile of NXD30001-mediated induction of Hsp gene expression differed in vivo from in vitro. NXD30001 induced expression of iHSP70 in skeletal muscle, cardiac muscle and, to a lesser extent, in kidney, but not in liver, spinal cord or brain with either single or repeated administration. NXD30001 is thus a useful experimental tool for culture work, but these data highlight the complex nature of Hsp gene regulation in vivo and the need for early evaluation of the efficacy of novel HSP inducers in target tissues. De par leur rôle dans le repliement des protéines, les protéines chaperonnes (HSPs) représentent des cibles thérapeutiques intéressantes pour le traitement des maladies neurodégéneratives, comme la sclérose latérale amyotrophique (ALS), caractérisés par la formation des agrégats protéiques. Les molécules inhibitrices de HSP90 sont des inducteurs de l'expression des gènes codant pour les HSPs notamment dans les neurones moteurs affectés dans l'ALS. Nous avons déterminé l'efficacité in vitro d'un nouvel inhibiteur de HSP90, le NXD30001, sur l'induction de l'expression de HSP40 et de HSP70 et son effet sur des mesures phénotypiques (agrégation protéique, fragmentation mitochondrial et mort neuronale) du à l'expression de SOD1 mutants. Cette étude se propose de déterminer les propriétés in vivo du NXD30001 en utilisant un modèle murin d'ALS. Les souris transgéniques SOD1G93A ont été traitées avec le NXD30001 délivré par injection intra-péritonéales (i.p.) afin de déterminer l'expression des gènes des protéines chaperonnes (HSP90, iHSP70, HSP60, HSP40 and HSP25) et la distribution tissulaire du NXD30001. La pénétrance tissulaire du NXD30001 dans le cerveau, la moelle…