Untersuchung der Wirkung des antiaggregativen Compounds anle138b auf Löslichkeit und Toxizität von mutierter SOD1

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the upper and lower motoneuron with flabby and spastic paralysis leading to death within three to five years because of respiratory insufficiency. 90% of the patients suffer spontaneous ALS and 10% have a hereditary genetic background also called familial ALS (fALS). Up to 23% of fALS are caused by mutations of Superoxide Dismutase 1 (SOD1), a highly conserved and ubiquitinated antioxidant enzyme. SOD1 positive intracellular Lewy-body-like hyaline inclusions in upper and lower motoneurons are a pathological hallmark of ALS patients, which lead to the nomenclature SOD-ALS. An increasing amount of these inclusions are also found in human SOD1 transgenic mice during progression of ALS conform symptoms which makes it a suitable ALS model. From other neurodegenerative diseases as Parkinson´s disease (α-synuclein), Alzheimer´s disease (tau) and Creutzfeldt Jakob disease (prion protein) we analogous know the correlation between protein aggregation and neuronal loss. Recent studies figured out anle138b, a di-pheny-pyracole derivative, as a compound reducing protein aggregation of α-synuclein, tau and prion protein which delays disease progression in relevant mouse models. In this study, we investigated the anti-aggregative effect of anle138b on mutated SOD1 (G85R, G93A, 127X) in cell culture and in the spinal cord of the ALS mouse model with human transgene SOD-G93A. Moreover, we performed histological analysis of the intumescentia lumbalis of the ALS mouse model to illuminate the neuroprotective effect for the lower motoneuron. We did not observe a sustainable reduction of protein aggregates in cell culture or in mouse model spinal cord. In contrast, protein aggregation rose exponentially with the age of the mice treated with anle138b. We also did not find an altered number of lower motoneurons in anle138b treated mice in comparison with placebo treated mice. In contrast to Parkinson´s disease, Alzheimer´s disease and Creutzfeldt Jakob disease, treatment with anle138b does not decrease protein aggregation in cell culture and in mouse model of SOD-ALS and does not provide a neuroprotective effect on lower motoneuron in mouse model of SOD-ALS.