Determining Selective Autophagy Kinase in Modulating Neurotoxicity in Huntington's Disease Model

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Zhenyu  Yue
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $453,906
Funding agency: National Institute of Neurological Disorders and Stroke

Our goal is to elucidate molecular mechanism for neuroprotective autophagy in Huntington's disease (HD) and
determine therapeutic potential for selective autophagy in treating the disease. HD is caused by an aberrant
expansion of CAG repeat (polyQ) in the HTT gene, which leads to a toxic gain-of-function in the mutant
huntingtin (mHTT) protein. Despite over 20 years' research, disease-modifying therapeutics is unavailable.
Thus, elucidation of the disease mechanism and mHTT clearance pathways is pivotal for the success of
therapeutic development. Autophagy is a catabolic cellular pathway that clears protein aggregates and injured
organelles through lysosomes as a quality control system. PolyQ-expanded protein aggregates including
fragments of HTT can be degraded by selective autophagy, and thus selective autophagy is considered a drug
target for HD. However, autophagy is a complex process subjected to tight regulation, and how exactly
autophagy selectively degrade mHTT remains poorly understood. We previously showed that ULK1 regulates
p62-mediated selective autophagy under proteotoxic stress. In the context of mHTT, however, we reported
dysregulation of ULK1 kinase activity that connects to reduced VPS34 activity and aberrant p62-selective
autophagy in the brains of HD model zQ175. Our current study suggests that ULK1 deficiency accelerates
mHTT-mediated toxicity. The data thus provides strong evidence for the role of ULK1-p62 mediated selective
autophagy in regulating mHTT toxicity. We hypothesize that ULK1 and p62 are promising modifiers of HD
disease progression. We propose (1) to determine the role and mechanism for ULK1-p62 signaling in the
degradation of mHTT through selective autophagy; (2) to investigate pathogenic mechanism that mHTT
disrupts ULK1 kinase activity and causes ULK1 deficiency-mediated selective autophagy impairment and
neurotoxicity; (3) determine ULK1 kinase activity as a therapeutic target to inhibit mHtt-mediated neurotoxicity
using animal models through genetic and pharmacological approaches. Our study is expected to reveal
molecular mechanism for ULK1 protective function against HD and validate ULK1 kinase activity as a drug
target for the clearance of mHTT and offering neuroprotection.

Terms: <Acceleration><Age><Agonist><Amino Acid Sequence><Animal Model><Animal Models and Related Studies><Antisense Agent><Antisense Oligonucleotides><Autophagocytosis><Axon><Bioavailability><Biological Availability><Biological Markers><Body Weight><Brain><Brain Nervous System><CAG repeat><CAG trinucleotide repeat><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell model><Cells><Cellular model><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complex><DNA><Data><Deoxyribonucleic Acid><Disease><Disease Progression><Disorder><Drug Targeting><Dysfunction><Encephalon><Functional disorder><GTF2H1><GTF2H1 gene><Gene Transcription><Genes><Genetic><Genetic Transcription><Goals><HD Gene><HD protein><Huntingtin><Huntingtin Protein><Huntington Chorea><Huntington Disease><Huntington gene><Huntington protein><Huntington's><Huntington's Disease><Huntington's disease gene product><Huntingtons Disease><IT15 gene><Impairment><Intracellular Communication and Signaling><Intranuclear Inclusion Bodies><Intranuclear Inclusions><KO mice><Kinases><Knock-in><Knock-out Mice><Knockout Mice><Lysosomes><Mediating><Mendelian disease><Mendelian disorder><Mendelian genetic disorder><Methods><Mice><Mice Mammals><Mitochondria><Molecular><Murine><Mus><NPC><Non-Polyadenylated RNA><Nuclear Inclusion><Nuclear Inclusion Bodies><Nuclear Pore Complex><Null Mouse><Oral><Organelles><P62 gene><P62 protein><Pathogenicity><Pathway interactions><Phenotype><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiologic Availability><Physiological><Physiopathology><Poly Q><Post-Transcriptional Gene Silencing><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranscriptional Gene Silencing><Posttranslational Modifications><Posttranslational Protein Processing><Primary Protein Structure><Process><Protein Modification><Proteins><Proteomics><Quality Control><RNA><RNA Expression><RNA Gene Products><RNA Interference><RNA Silencing><RNA Splicing><RNAi><Refractory><Regulation><Reporting><Research><Resistance><Ribonucleic Acid><Role><Scaffolding Protein><Sequence-Specific Posttranscriptional Gene Silencing><Signal Transduction><Signal Transduction Systems><Signaling><Splicing><Stress><Symptoms><Synapses><Synaptic><System><TFIIH gene><TFIIH protein><Techniques><Testing><Therapeutic><Toxic effect><Toxicities><Toxicity Testing><Toxicity Tests><Transcription><Transphosphorylases><ages><antisense oligo><autophagy><bio-markers><biologic marker><biological signal transduction><biomarker><disease model><disorder model><excitotoxic><excitotoxicity><gain of function><improved><injured><insoluble aggregate><interesting transcript 15><knockin><mitochondrial><model of animal><monogenic disease><monogenic disorder><mouse model><murine model><mutant><neuron toxicity><neuronal toxicity><neuroprotection><neuroprotective><neurotoxicity><novel><overexpress><overexpression><oxidative damage><oxidative injury><pathophysiology><pathway><pharmacologic><polyQ><polyglutamine><postnatal><prevent><preventing><protein aggregate><protein aggregation><protein homeostasis><protein sequence><proteostasis><proteotoxic><proteotoxicity><resistant><response><single-gene disease><single-gene disorder><small molecule><social role><success><synapse><therapeutic agent development><therapeutic development><therapeutic target><trafficking>