Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington’s disease

Abstract

Huntington's disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin. These excessive repeats confer a toxic gain of function on huntingtin, which leads to the degeneration of striatal and cortical neurons and a devastating motor, cognitive, and psychological disorder. Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD. We previously demonstrated that viral delivery of glial cell line-derived neurotrophic factor (GDNF) provides structural and functional neuroprotection in a rat neurotoxin model of HD. In this report we demonstrate that viral delivery of GDNF into the striatum of presymptomatic mice ameliorates behavioral deficits on the accelerating rotorod and hind limb clasping tests in transgenic HD mice. Behavioral neuroprotection was associated with anatomical preservation of the number and size of striatal neurons from cell death and cell atrophy. Additionally, GDNF-treated mice had a lower percentage of neurons containing mutant huntingtin-stained inclusion bodies, a hallmark of HD pathology. These data further support the concept that viral vector delivery of GDNF may be a viable treatment for patients suffering from HD.gene therapy ͉ neurodegeneration ͉ neuroprotection ͉ polyglutamine ͉ adenoassociated virus H untington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from an expanded trinucleotide (CAG: cytosine, adenine, and guanine) repeat at the IT15 locus on chromosome 4 (1) within the huntingtin gene. The abnormal DNA is translated into mutant huntingtin with an expanded glutamine stretch at the N terminus of the protein. The excessive number of glutamine repeats is responsible for the misfolding of huntingtin and the subsequent formation of neuronal inclusions, degeneration of striatal and cortical neurons, and a triad of symptoms including severe motor, cognitive, and psychological disturbances that are ultimately fatal.To date, HD remains incurable. Several therapies have yielded positive results in animal models, including those that alleviate potential glutamate-induced excitotoxicity such as riluzole and remacemide (2-4); those that increase the production of energy in the form of ATP in the cell, including creatine and coenzyme Q 10 (5-9); those that inhibit caspase activation and apoptosis, such as minocycline (10, 11); and those that aim at replacing degenerating cells by means of fetal tissue transplantation (12-18). However, when tested clinically, none has made a major impact in the symptomatic treatment of HD, nor have any demonstrated the ability to alter the natural history of the disease by preventing cell death.Genetic testing can identify mutated gene carriers destined to suffer from HD. Unlike other neurodegenerative disorders, identification of the genetic marker provides the unique opportunity to intercede therapeutically before the onset of symptoms that result from n...

Mutant huntingtin can paradoxically protect neurons from death

“…[46][47][48] Although several other interesting studies have demonstrated potential neuroprotective properties of different factors investigated in the context of HD, none of these factors have afforded the same dramatic protection against excitotoxicity as is in the transgenic HD mouse models we have described in this review article (see e.g. Saydoff et al, 49 Dedeoglu et al, 50 McBride et al, 51 Jin et al 52 and Ferrante et al 53 ).…”

Lesion-Induced Increase in Survival and Migration of Human Neural Progenitor Cells Releasing GDNF

“…GDNF has been shown to protect both dopamine neurons and striatal neurons undergoing degeneration in models of Parkinson's and Huntington's disease when delivered directly to the striatum of primates and rodents using in vivo gene therapy approaches (14,16,19) Ex vivo approaches in which stem cells are modified to release GDNF and then transplanted offer an interesting alternative that does not require the injection of live virus to the brain. However, to achieve widespread delivery of GDNF, it will be necessary for the cells to migrate and integrate across wide areas.…”

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

“…First, compared with glial cells, lower and impaired neuronal ubiquitin-proteasome system activity, which plays a critical role in clearing misfolded proteins [18] , may account for the preferential accumulation of misfolded Htt in neurons as well as their selective vulnerability [19][20][21] . Second, the expression of mutant huntingtin in glial cells, which could clear excess excitatory neurotransmitters from extracellular space, contributed to neuronal excitotoxicity [2,5,22,23] .…”