New Insight into HDAC1 as a Molecular Linker between Neurodegeneration and Circadian Clocks

Description

Neurodegenerative diseases in the central nervous system (CNS) including Parkinson’s (PD),Alzheimer’s (AD), and Huntington’s (HD) diseases affect millions of people worldwide. However,there is no cure yet because regeneration of the CNS neurons is extremely rare. Therefore, whenneurodegeneration is diagnosed, it is important to stop the progress immediately to reduce furtherdamages and have a chance to keep and recover neuronal functions. Our previous works about molecular mechanisms of neurodegeneration and circadian clockssuggest a well-known transcriptional corepressor, histone deacetylase 1 (HDAC1), as a molecularlinker between them. HDAC1 nuclear export was induced during neurodegeneration and resultedin a decreased level of HDAC1 in the nucleus. We also found that HDAC1 depletion disruptedcircadian clocks which are built on a transcriptional negative feedback loop. Circadian clocks areendogenous oscillators and regulate thousands of gene expression to control diverse cellularprocesses and signaling pathways to drive daily biological rhythms. Therefore, disrupted circadianclocks can be involved in diverse human diseases through altered transcription. Recent numerousstudies have reported disrupted circadian clocks in patients with PD, AD, and HD. Also, neuronaldisconnectivity by degeneration of pre-synapses was observed in mouse lines lacking the coreclock genes. However, no study has provided a molecular linker and underlying mechanisms toexplain how disrupted circadian clocks are involved in neurodegeneration.Previously, we addressed two points: a decreased level of nuclear HDAC1 duringneurodegeneration and HDAC1 depletion resulted in disrupted circadian clocks to change geneexpression. Based on our previous works, we hypothesize that neurodegeneration disruptscircadian clocks to accelerate its own progress. To test this, we will focus on three majorobjectives: 1) Confirm that HDAC1 nuclear export during neurodegeneration disrupts circadianclocks; 2) Test objective 1) in different types of neurons to address whether this is a generic orneuron type-specific event; 3) Define whether disrupted circadian clocks accelerate or delay theprogress of neurodegeneration. From this project, we will get a clear evidence to provide amolecular linker between neurodegeneration and circadian clocks and address how disruptedcircadian clocks are involved in the progress of neurodegeneration.?