Mitigating aberrant Cdk5 activation alleviates mitochondrial defects and motor neuron disease symptoms in spinal muscular atrophy. Proc Natl Acad Sci U S A 2023 Nov 21;120(47):e2300308120
Date
11/17/2023Pubmed ID
37976261Pubmed Central ID
PMC10666147DOI
10.1073/pnas.2300308120Scopus ID
2-s2.0-85177422314 (requires institutional sign-in at Scopus site)Abstract
Spinal muscular atrophy (SMA), the top genetic cause of infant mortality, is characterized by motor neuron degeneration. Mechanisms underlying SMA pathogenesis remain largely unknown. Here, we report that the activity of cyclin-dependent kinase 5 (Cdk5) and the conversion of its activating subunit p35 to the more potent activator p25 are significantly up-regulated in mouse models and human induced pluripotent stem cell (iPSC) models of SMA. The increase of Cdk5 activity occurs before the onset of SMA phenotypes, suggesting that it may be an initiator of the disease. Importantly, aberrant Cdk5 activation causes mitochondrial defects and motor neuron degeneration, as the genetic knockout of p35 in an SMA mouse model rescues mitochondrial transport and fragmentation defects, and alleviates SMA phenotypes including motor neuron hyperexcitability, loss of excitatory synapses, neuromuscular junction denervation, and motor neuron degeneration. Inhibition of the Cdk5 signaling pathway reduces the degeneration of motor neurons derived from SMA mice and human SMA iPSCs. Altogether, our studies reveal a critical role for the aberrant activation of Cdk5 in SMA pathogenesis and suggest a potential target for therapeutic intervention.
Author List
Miller N, Xu Z, Quinlan KA, Ji A, McGivern JV, Feng Z, Shi H, Ko CP, Tsai LH, Heckman CJ, Ebert AD, Ma YCAuthor
Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCyclin-Dependent Kinase 5
Disease Models, Animal
Humans
Induced Pluripotent Stem Cells
Mice
Motor Neurons
Muscular Atrophy, Spinal
Nerve Degeneration
Survival of Motor Neuron 1 Protein
