Department of  Neurosurgery
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Current Research — Yano Lab

The age-dependent dysfunction and progressive loss of selective neurons are key characteristics of neurodegenerative disorders, including Huntington’s disease (HD).  HD is a devastating fatal neurodegenerative disease characterized by selective neuronal loss in the striatum and cortex due to an aberrant polyglutamine expansion in the huntingtin protein.  Disease symptoms include abnormal body movements, cognitive decline, and psychiatric disorders.  Despite intensive efforts to identify the molecular mechanisms of neuronal death in HD, no curative treatments are currently available.  Our laboratory research interest is to understand at the molecular level how mutant huntingtin drives abnormal cellular changes, with a particular focus on transcriptional dysregulation and mitochondrial dysfunction, and how these changes lead to neuronal death and dysfunction. 

Transcriptional dysregulation in Huntington’s disease

Altered gene expression in the brain is an early abnormality in the course of HD progression and is thought to play a central role in the pathogenesis of this disease.  Emerging evidence suggests that epigenetic mechanisms, including DNA methylation and posttranslational modification of histones, which influence chromatin structure, play important roles in the transcriptional dysregulation observed in HD.  Our underlying hypothesis is that epigenetic dysregulation of genes important for neuronal function and survival causes neuronal dysfunction and death in HD.  The current objectives in our laboratory are 1) to identify critical transcripts altered in HD neurons using postmitotic neuronal culture and animal models of the disease, 2) to identify novel epigenetic mechanisms that drive key gene expression changes and subsequently cause neuronal dysfunction and death, and 3) to test the effect of pharmacological and genetic manipulation of disease-specific epigenetic pathways on the behavior and survival of HD transgenic mice, all with the aim of identifying potential therapies for human HD.  Given that HD has psychiatric manifestations, including anxiety and depression, we are also interested in identifying treatments to ameliorate these symptoms through animal behavioral studies.  To achieve these research objectives, we use a diverse set of techniques, including lentivirus-mediated gene expression and RNA interference, recently developed next-generation sequencing technology for genome-wide transcriptome and epigenome analyses, and high-throughput epigenetic-focused drug library screen using a primary neuron model of HD.  Our long-term goal is to develop novel epigenetics-directed therapies to prevent or slow the progression of neurodegenerative disease.

Mitochondrial dysfunction in Huntington’s disease

In addition to transcriptional dysregulation, another important cellular alteration that is believed to be associated with neuronal loss in HD is mitochondrial dysfunction.  However, the mechanisms driving mitochondrial dysfunction and neurodegeneration in HD remain largely unknown.  We recently discovered a mechanism by which mutant huntingtin directly impairs mitochondrial protein import through an interaction with the TIM23 import machinery.  We also demonstrated that defective TIM23-dependent protein import triggers mutant Htt-induced mitochondrial neuronal death.  These findings suggest the intriguing possibility that restoration of mitochondrial protein import represents a novel therapeutic strategy for HD and other neurodegenerative diseases, which exhibit deficient mitochondrial protein import.