Affiliation:
1. Department of Neurology Seoul National University Hospital Seoul Republic of Korea
2. Department of Neurology Chungbuk National University Hospital Cheongju‐si Chungcheongbuk‐do Republic of Korea
3. Department of Translational Medicine Seoul National University College of Medicine Seoul Republic of Korea
4. Department of Neurology Seoul National University College of Medicine Seoul Republic of Korea
5. Neuroscience Research Institute Seoul National University College of Medicine Seoul Republic of Korea
Abstract
AbstractDeregulated cyclin‐dependent kinase 5 (Cdk5) activity closely correlates with hyperphosphorylated tau, a common pathology found in neurodegenerative diseases. Previous postmortem studies had revealed increased Cdk5 immunoreactivity in amyotrophic lateral sclerosis (ALS); hence, we investigated the effects of Cdk5 inhibition on ALS model mice and neurons in this study. For the in vitro study, motor neuron cell lines with wild‐type superoxide dismutase 1 (SOD1) or SOD1G93A and primary neuronal cultures from SOD1G93A transgenic (TG) mice or non‐TG mice were compared for the expression of proteins involved in tau pathology, neuroinflammation, apoptosis, and neuritic outgrowth by applying Cdk5‐small interfering RNA or Cdk5‐short hairpin RNA (shRNA). For the in vivo study, SOD1G93A mice and non‐TG mice were intrathecally injected with adeno‐associated virus 9 (AAV9)‐scramble (SCR)‐shRNA or AAV9‐Cdk5‐shRNA at the age of 5 weeks. Weight and motor function were measured three times per week from 60 days of age, longevity was evaluated, and the tissues were collected from 90‐day‐old or 120‐day‐old mice. Neurons with SOD1G93A showed increased phosphorylated tau, attenuated neuritic growth, mislocalization of SOD1, and enhanced neuroinflammation and apoptosis, all of which were reversed by Cdk5 inhibition. Weights did not show significant differences among non‐TG and SOD1G93A mice with or without Cdk5 silencing. SOD1G93A mice treated with AAV9‐Cdk5‐shRNA showed significantly delayed disease onset, delayed rotarod failure, and prolonged survival compared with those treated with AAV9‐SCR‐shRNA. The brain and spinal cord of SOD1G93A mice intrathecally injected with AAV9‐Cdk5‐shRNA exhibited suppressed tau pathology, neuroinflammation, apoptosis, and an increased number of motor neurons compared to those of SOD1G93A mice injected with AAV9‐SCR‐shRNA. Cdk5 inhibition could be an important mechanism in the development of a new therapeutic strategy for ALS.image
Funder
National Research Foundation of Korea