Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis.
Previous studies suggest that neurotrophins support regeneration and survival of injured motoneurons. Based on these findings, brain-derived neurotrophic factor (BDNF) has been clinically investigated for its therapeutic potential in amyotrophic lateral sclerosis (ALS), a rapidly progressing and fatal motoneuronal disease. We questioned whether imbalances of neurotrophic levels are indeed involved in the pathology of ALS. Therefore the expression of nerve growth factor (NGF), BDNF, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) was investigated in postmortem muscle tissue of the biceps from 15 patients with neuropathologically confirmed sporadic ALS and 15 age-matched controls. Using mRNA analysis techniques and quantitative protein measurements, we have demonstrated that both mRNA and protein levels of all four neurotrophins are increased in muscle tissue of ALS patients. The production levels displayed a disease duration dependency and different expression patterns emerged for the four neurotrophins. Whereas the early phase of the disease was characterized by a strong upregulation of BDNF, levels of NGF, NT-3, and NT-4/5 gradually increased in the course of the disorder, peaking at later stages. We conclude that decreased neurotrophic support from muscle tissue is most likely not the cause of motoneuron degeneration in ALS. On the contrary, our results suggest that degenerating motoneurons in ALS are exposed to elevated levels of muscle-derived neurotrophins.
Küst
B M
BM
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Copray
J C V M
JC
Brouwer
N
N
Troost
D
D
Boddeke
H W G M
HW
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D012333:RNA, Messenger; D020932:Nerve Growth Factor; C073922:neurotrophin 4