Biomarkers in the assessment of therapies for familial amyloidotic polyneuropathy.
The identification of specific biomarkers provides opportunities to develop early diagnostic parameters, monitor disease progression, and test drug efficiency in clinical trials. We previously demonstrated that in familial amyloidotic polyneuropathy (FAP) related to the abnormal extracellular tissue deposition of mutant transthyretin (TTR), inflammatory and apoptotic pathways are triggered in the presymptomatic stages of the disease, when nonfibrillar TTR deposits are present. In the present work, to better define biomarkers for future assessment of prophylactic and therapeutic drugs in the treatment of FAP, we extended the search for oxidative stress and apoptotic biomarkers to clinical samples and animal models presenting nonfibrillar and fibrillar TTR. We found that lipid peroxidation measured by hydroxynonenal, oxidative DNA damage measured by 8-hydroxy-2'-deoxyguanosine, and cellular redox homeostasis measured by glutaredoxin 1 were consistently increased in biopsy specimens from FAP patients and in tissues from transgenic mouse models presenting nonfibrillar TTR deposition. Death-receptor Fas, caspase-8, and Bax were also found to be increased, indicative of the involvement of death receptors in the observed apoptosis process. Removal of TTR deposition by an immunization protocol resulted in significant decreases of the selected markers we describe, corroborating the relationship between TTR deposition, oxidative stress, and apoptosis. Taken together, our results provide a robust biomarker profile for initial experimental animal studies and clinical trials to assess the application of the selected markers in therapies aimed at removal and/or inhibition of TTR polymerization.
Macedo
Bárbara
B
Molecular Neurobiology, Instituto de Biologia Molecular e Celular, Porto, Portugal.
Batista
Ana Rita
AR
do Amaral
José Barbas
JB
Saraiva
Maria João
MJ
D028226:Amyloidosis, Familial / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism*; D004249:DNA Damage; D007150:Immunohistochemistry; D051379:Mice; D018384:Oxidative Stress; D011115:Polyneuropathies / Q000378:metabolism / Q000628:therapy*; D011228:Prealbumin / Q000378:metabolism
D015415:Biomarkers; D011228:Prealbumin