Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice

10.1016/j.nbd.2014.12.030Neurobiology of Disease7624-3

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

Aguilar Salegio et al. demonstrate the feasibility of expressing a secreted protein in the CNS of nonhuman primates. Specifically, they use magnetic resonance imaging to enhance the delivery of an AAV2 vector encoding human acid sphingomyelinase tagged with a viral hemagglutinin epitope (AAV2-hASM-HA). This approach led to global transduction of highly interconnected CNS regions such as the brainstem and thalamus

IPSC-derived neurons from GBA1-associated Parkinson's disease patients show autophagic defects and impaired calcium homeostasis

Mutations in the acid \u3b2 2-glucocerebrosidase (GBA1) gene, responsible for the lysosomal storage disorder Gaucher s disease (GD), are the strongest genetic risk factor for Parkinson s disease (PD) known to date. Here we generate induced pluripotent stem cells from subjects with GD and PD harbouring GBA1 mutations, and differentiate them into midbrain dopaminergic neurons followed by enrichment using fluorescence-activated cell sorting. Neurons show a reduction in glucocerebrosidase activity and protein levels, increase in glucosylceramide and \uce\ub1-synuclein levels as well as autophagic and lysosomal defects. Quantitative proteomic profiling reveals an increase of the neuronal calcium-binding protein 2 (NECAB2) in diseased neurons. Mutant neurons show a dysregulation of calcium homeostasis and increased vulnerability to stress responses involving elevation of cytosolic calcium. Importantly, correction of the mutations rescues such pathological phenotypes. These findings provide evidence for a link between GBA1 mutations and complex changes in the autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration