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Mechanisms of HIPK2 in neurodegeneration

HIPK2在神经退行性变中的机制

基本信息

批准号：
9188763
负责人：
Eric J Huang
金额：
$ 34.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9188763
关键词：
Address Adult Affect Amyotrophic Lateral Sclerosis Antibodies Axon Axonal Transport Biochemical Bioenergetics Brain CCL4 gene Candidate Disease Gene Cell Death Cells Clinical DNA Sequence Alteration Data Defect Disease Disease Progression Embryo Familial Amyotrophic Lateral Sclerosis Fibroblasts Functional disorder Gene Expression Gene Targeting Genes Genetic Homeostasis Link MAPK8 gene Mediating Mitochondria Modeling Molecular Motor Neurons Mus Muscular Atrophy Mutagenesis Nerve Degeneration Neurodegenerative Disorders Neurons Onset of illness Pathogenesis Pathway interactions Patients Peptide Mapping Phenotype Phosphorylation Phosphotransferases Pre-Clinical Model Protein Kinase Proteins RNA Resistance Role Serine Spinal Spinal Cord Symptoms Synapses Testing Threonine Tissue Sample Tissues Toxic effect Transcriptional Regulation Transgenic Mice Ubiquitin endoplasmic reticulum stress homeodomain human disease improved in vitro Model insight kinase inhibitor lateral column motor neuron degeneration mouse model multicatalytic endopeptidase complex multidisciplinary mutant neuron loss parkin gene/protein phosphoproteomics protein TDP-43 protein metabolism protein misfolding therapeutic target transcriptome

项目摘要

PROJECT SUMMARY Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is an adult-onset neurodegenerative disease that affects upper and lower motor neurons. The key clinical features in ALS patients include muscle wasting, and progressive loss of spinal motor neurons and upper motor neurons and their axons in the lateral columns of the spinal cord. The past 10 years have witnessed a tremendous expansion in the molecular mechanisms of this devastating disease thanks to the discoveries of genetic mutations that are causally linked to both familial ALS (FALS) and sporadic ALS (SALS). Characterizations of these “ALS disease genes” suggest that dysfunctions in protein homeostasis via the ubiquitin-proteasome pathways (proteostasis) might contribute to the pathogenesis and disease progression in ALS. Consistent with the genetic data, a key pathological feature in FALS and SALS is accumulation of misfolded proteins in motor neurons, which disrupts normal neuronal functions, including axonal transport, mitochondrial bioenergetics, gene expression, and synaptic connectivity. Persistent accumulation of misfolded proteins eventually triggers endoplasmic reticulum (ER) stress-induced cell death, which leads to neurodegeneration through mechanisms that are poorly understood. This proposal focuses on the neuronal cell death mechanism downstream of the IRE1α pathway of ER stress. We show that ER stress, induced pharmacologically or by mutant SOD1 proteins, activates a highly conserved kinase HIPK2 (homeodomain interacting protein kinase 2) to promote neuronal cell death. Biochemical evidence shows that HIPK2 acts downstream of IRE1α-ASK1 and upstream of JNK to promote ER stress-mediated cell death. In addition, proteomics, phospho-peptide mapping and mutagenesis further show that ER stress activates HIPK2 by promoting phosphorylation on specific Serine and Threonine residues within the kinase domain. Using phospho-HIPK2-specific antibodies, we show that HIPK2 activation in the spinal cord precedes symptom onset in SOD1G93A mice. Importantly, loss of HIPK2 in SOD1G93A;Hipk2-/- mice mitigates neurodegeneration, delays disease onset and prolongs survival. Finally, we have extended our findings of HIPK2 in ER stress to human disease using a large number of spinal cord tissues from FALS and SALS patients. Together, these results support the hypothesis that HIPK2 is an essential target in the downstream of IRE1α pathway that promotes ER stress-induced neuronal cell death in ALS. We propose three multidisciplinary Aims to investigate the robust, yet previously unappreciated role of HIPK2 in ER stress-induced cell death mechanism in ALS. Results from these studies will not only address a major challenge in understanding disease mechanism in ALS, they will also provide new directions to develop potential therapeutic targets to mitigate neuronal cell death in ALS.

项目总结