Muscle-derived but not centrally derived transgene GDNF is neuroprotective in G93A-SOD1 mouse model of ALS Wen Li a , Danielle Brakefield a , Yanchun Pan a , Dan Hunter b , Terence M. Myckatyn b , Alexander Parsadanian a, ⁎ a Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, Box 8518, St. Louis, MO 63110, USA b Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA Received 1 May 2006; revised 27 July 2006; accepted 29 August 2006 Available online 10 October 2006 Abstract Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MNs), and is considered a potential agent for the treatment of amyotrophic lateral sclerosis (ALS) and other MN diseases. The effectiveness of GDNF may depend significantly upon its route of delivery to MNs. In this study we tested the neuroprotective effects of target-derived and centrally derived GDNF in the G93A-SOD1 mouse model of ALS using a transgenic approach. We found that overexpression of GDNF in the skeletal muscle (Myo-GDNF mice) significantly delayed the onset of disease and increased the life span of G93A-SOD1 mice by 17 days. The duration of disease also increased by 8.5 days, indicating that GDNF slowed down the progression of disease. Locomotor performance in Myo-GDNF/G93A-SOD1 mice was also significantly improved. The behavioral improvement correlated well with anatomical and histological data. We demonstrated that muscle-derived GDNF resulted in increased survival of spinal MNs, and twice as many MNs survived in end-stage double transgenic mice compared to end-stage G93A- SOD1 mice. Muscle-derived GDNF also had profound effects on muscle innervation and axonal degeneration. Significantly higher numbers of completely or partially innervated NMJs and large caliber myelinated axons were found in double transgenic mice. In contrast, we demonstrated that overexpression of GDNF in astrocytes in the CNS (GFAP-GDNF mice) failed to demonstrate any neuroprotective effects in G93A-SOD1 mice both on behavioral and histological levels. These data indicate that retrograde transport and signaling of GDNF is more physiological and effective for ALS treatment than anterogradely transported GDNF. © 2006 Elsevier Inc. All rights reserved. Keywords: ALS; Motoneuron; GDNF; Survival; Transgenic Introduction Amyotrophic lateral sclerosis (ALS) is a progressive, adult onset neurodegenerative disease that mainly causes the selective loss of upper and lower MNs, and leads to muscular atrophy, respiratory failure and eventual death of patients within a few years after onset of disease (Sejvar et al., 2005). The majority of ALS cases are sporadic with no genetic link. Approximately 5– 10% of ALS cases are inherited and about 20% of familial ALS (FALS) cases are linked to autosomal dominant mutations in the SOD1 gene (Nirmalananthan and Greensmith, 2005). Since the identification of the first mutation (Rosen et al., 1993) more than 100 new mutations have been described throughout the SOD1 gene (Andersen et al., 2003). Significant progress has been made in recent years in understanding the neuropathology and mechanisms of FALS, and it is apparent now that ALS is a very complex and multifunctional disease, making the disco- very of pharmacological agents for treatment challenging (Bruijn et al., 2004; Shaw, 2005). Riluzole is currently the only FDA-approved drug that has some beneficial effects in ALS patients, but its effects are rather modest (Bruijn et al., 2004; Nirmalananthan and Greensmith, 2005). Based on their in vitro and in vivo ability to promote the survival of MNs, neurotrophic factors (NFs) of different families have been considered as potential agents for the treatment of MN diseases, including ALS. However, several NFs such as CNTF, BDNF and IGF-1 failed to demonstrate any Experimental Neurology 203 (2007) 457 – 471 www.elsevier.com/locate/yexnr ⁎ Corresponding author. Fax: +1 314 658 3999. E-mail address: parsadaniana@neuro.wustl.edu (A. Parsadanian). 0014-4886/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2006.08.028