is in the public domain in the US. The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1

Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model

Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model

The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1

The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1

Transcriptional dysregulation of TrkA associates with

with neurodegeneration in spinocerebellar

Spinocerebellar ataxia type 1 (SCA1) is an adult onset, autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in ataxin-1, which encodes the ataxin-1 protein. SCA1 is one of nine polyQ-expansion gain-of-function diseases which includes Huntington’s disease, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy and other ataxias. Clinical symptoms of SCA1 include ataxia, dysarthria, ophthalmoparesis, muscle wasting, and extrapyramidal and bulbar dysfunction. Cerebellar Purkinje cells (PCs), neurons in the inferior olive and nuclei of the brainstem are affected. No disease-modifying therapy exists for SCA1. The goals of my thesis were to assess the safety and efficacy of AAV-delivered artificial miRNAs targeting ataxin-1 to alleviate neuropathological and behavioral phenotypes in the knock-in and transgenic SCA1 mouse models. In the knock-in SCA1 mouse model I delivered AAVs expressing an artificial miRNA (miSCA1) targeting sequences conserved in mouse and human ataxin-1 directly to the deep cerebellar nuclei. This achieved long term silencing of ataxin-1 mRNA and

A polyglutamine expansion disease protein

Wallerian degeneration refers to a loss of the distal part of an axon after nerve injury. Wallerian degeneration slow (Wld s) mice overexpress a chimeric protein containing the NAD synthase NMNAT (nicotinamide mononucleotide adenylyltransferase 1) and exhibit a delay in axonal degeneration. Currently, conflicting evidence raises questions as to whether NMNAT is the protecting factor and whether its enzymatic activity is required for such a possible function. Importantly, the link between nmnat and axon degeneration is at present solely based on overexpression studies of enzymatically active protein. Here we use the visual system of Drosophila as a model system to address these issues. We have isolated the first nmnat mutations in a multicellular organism in a forward genetic screen for synapse malfunction in Drosophila. Loss of nmnat causes a rapid and severe neurodegeneration that can be attenuated by blocking neuronal activity. Furthermore, in vivo neuronal expression of mutated nmnat shows that enzymatically inactive NMNAT protein retains strong neuroprotective effects and rescues the degeneration phenotype caused by loss of nmnat. Our data indicate an NAD-independent requirement of NMNAT for maintaining neuronal integrity that can be exploited to protect neurons from neuronal activity-induced degeneration by overexpression of the protein.