Site Specific Modification of Adeno-Associated Virus Enables Both Fluorescent Imaging of Viral Particles and Characterization of the Capsid Interactome.

Adeno-associated viruses (AAVs) are attractive gene therapy vectors due to their low toxicity, high stability, and rare integration into the host genome. Expressing ligands on the viral capsid can re-target AAVs to new cell types, but limited sites have been identified on the capsid that tolerate a peptide insertion. Here, we incorporated a site-specific tetracysteine sequence into the AAV serotype 9 (AAV9) capsid, to permit labelling of viral particles with either a fluorescent dye or biotin.

Gene Therapy in the Nervous System: Failures and Successes.

Genetic disorders, caused by deleterious changes in the DNA sequence away from the normal genomic sequence, affect millions of people worldwide. Gene therapy as a treatment option for patients is an attractive proposition due to its conceptual simplicity. In principle, gene therapy involves correcting the genetic disorder by either restoring a normal functioning copy of a gene or reducing the toxicity arising from a mutated gene.

Disc1 variation leads to specific alterations in adult neurogenesis.

Disrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense Disc1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that Disc1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. Disc1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while Disc1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus.

DJ-1 is essential for long-term depression at hippocampal CA1 synapses.

Mutations in DJ-1 cause inherited Parkinson's disease (PD) in several families. The normal function of DJ-1 is unknown, but mice lacking DJ-1 exhibit a deficit in dopaminergic signaling in the striatum. Since the hippocampus contains relatively high levels of DJ-1, and PD patients are often cognitively impaired, we evaluated the effects of DJ-1 deficiency on the plasticity of hippocampal CA1 synapses.

Progressive behavioral deficits in DJ-1-deficient mice are associated with normal nigrostriatal function.

Loss-of-function mutations in the DJ-1 gene account for an autosomal recessive form of Parkinson's disease (PD). To investigate the physiological functions of DJ-1 in vivo, we generated DJ-1 knockout (DJ-1(-/-)) mice. Younger (<1 year) DJ-1(-/-) mice were hypoactive and had mild gait abnormalities.