Browsing by Author "Korpelainen, Anna"

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease in which both upper and lower motor neurons degenerate gradually. The disease leads to a total paralysis of almost all skeletal muscles and to death within 3-5 years after onset. At the moment there are two disease modifying medicines available, riluzole and edaravone. Neither is able to cure the disease or even to stop or remarkably slow down its progression. Endoplasmic reticulum (ER) stress has been proposed as one of the pathophysiological mechanisms underlying ALS. During ER stress misfolded of unfolded proteins accumulate in ER lumen. As a defense mechanism, the cell launches unfolded protein response (UPR). UPR response aims to reduce the protein load in ER and restore cell’s normal functions. If the damage is already beyond repair, UPR signal cascades lead to programmed cell death. Neurotrophic factors (NTFs) regulate the growth of nervous tissue and participate in repairing processed. Many of the known NTFs have first seemed promising in the preclinical models of ALS but however failed in clinical trials. Cerebral dopamine neurotrophic factor (CDNF) differs drastically both in structure and function from conventional NTFs. CDNF has seen to relieve ER stress and improve motor behavior in the animal models of Parkinsons’s disease. Recently CDNF entered clinical trials in Parkinson’s patients. Since ER stress is believed to be present not only in ALS but also in Parkinson’s disease and other neurodegenerative diseases, it might have an effect in treating ALS patients. SOD1-G93A is a well-established animal model of ALS in which the animals show typical motor impairments comparable to human disease. In this study we used a novel mouse line obtained from crossing traditional SOD1-G93A model and CDNF knock out models. The study aimed to evaluate the effect of endogenic CDNF loss in survival, onset of symptoms, motor behavioral and spinal motor neuron degeneration in the new line. ER-stress and autophagy marker levels were studied with quantitative polymerase chain reaction (CNDF) and western blotting techniques. Spinal motor neuron loss was examined by anti-choline acetyltransferase antibody (ChAT) stainings. SOD1-G93A CDNF knock out animals were observed to have more severe motor impairments in the early stages of the disease compared to the traditional SOD1-G93A mice. In addition, the degeneration of spinal motor neurons appeared to be more severe in the new line. There were no statistically significant differences in ER stress between the genotypes although a trend of increased ER stress was observed. Endogenous CDNF loss had no effect on the healthy animals. The results suggest that CNDF is a potential treatment for ALS and it might have only little side effect since it does not seen to affect healthy tissue. In medical usage, CDNF might be most effective when administered immediately after disease onset. However, this might be difficult because of the challenges in ALS diagnosis.