GDNF levels regulate lumbar motor neuron physiology and determine life expectancy in limb-onset ALS
olfat, s.; Choopanian, P.; Matlik, K.; Mirzaie, M.; Andressoo, J.-O.
Show abstract
Approximately one-third of amyotrophic lateral sclerosis (ALS) patients die within 12 months, while up to 10% live more than a decade. The factors driving this variation remain unclear but may elucidate disease mechanisms and guide therapy development. Here, we analyzed raw postmortem RNA-seq datasets from ALS patients and controls to quantify glial cell line-derived neurotrophic factor (GDNF) expression across cervical (n=161), thoracic (n=44), and lumbar (n=143) spinal cord regions. GDNF levels varied several-fold between individuals and correlated with motor neuron marker gene expression specifically in the lumbar spinal cord, but not in thoracic or cervical regions. In 76 limb-onset ALS patients, higher lumbar GDNF expression correlated with longer survival, whereas no such relationship was observed in 32 bulbar-onset patients. To test causality, we used the GDNF hypermorph SOD1G93A mouse model, in which [~]30% (skeletal muscle) and 2-fold (spinal cord) GDNF overexpression enhanced neuromuscular junction (NMJ) preservation and improved motor function for 10-13 weeks, equating to [~]8-10 years in human life expectancy. In contrast, previous ectopic GDNF applications yielded only transient benefit. These findings identify endogenous lumbar GDNF levels as a determinant of life expectancy in limb-onset ALS and suggest that strategies to stimulate GDNF signalling may slow disease progression, with potentially the greatest benefit in leg-onset patients.
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