Alzheimer  >   A. The Pathogenesis of Huntington's Disease

Huntington's disease (HD) exhibits wide variety of symptoms (Roos, 2010) similar to other neurodegenerative disorders, such as motor symptoms (Parkinson's disease), dementia (Alzheimer's disease and frontotemporal dementia) and depression. HD is caused by the mutation of the protein, huntingtin (encoded by the HTT gene), whose normal function is to enhance the transport of BDNF-containing vesicles from the cell body to synapses (Gauthier et al., 2004).

Huntington's Disease Is a 4-repeat Tauopathy

The BDNF released from synaptic vesicles can stimulate its own production via binding with TrkB in the synaptic membrane (Zheng and Wang , 2009; Cunha et al., 2010). Hence, impairment of the BDNF transport to synapses may cause BDNF deficiency, which has been observed in HD (Zuccato and Cattaneo, 2007). BDNF deficiency may lead to miR-132 down-regulation (Chapter 12), which has also been confirmed in HD (Johnson and Buckley, 2009; Lee et al., 2011; Wanet et al., 2012). The miR-132 down-regulation promotes 4-repeat (4R) Tau and total Tau production (Smith et al., 2011). Furthermore, the mutant huntingtin contains expanded glutamine repeats, capable of interacting with the splicing factor SRSF6, leading to increased 4R and total Tau level (Fernández-Nogales et al., 2014).

Selective Vulnerability

Huntingtin is expressed ubiquitously across the brain, but only a number of brain regions are selectively affected by its mutation. Among them, striatum is the most severe (Landwehrmeyer et al., 1995), partly due to its heavy dependence on BDNF transport (Zhao et al., 2016). Other areas impaired by HD include EC (Braak and Braak, 1992), and cerebral cortex (Vuono et al., 2015), particularly the primary motor cortex and anterior cingulate cortex (ACC) (Thu et al., 2010). In HD, the Tau pathology was observed in EC, striatum and cerebral cortex (McIntosh et al., 1978; Vuono et al., 2015; Gratuze et al., 2016).

According to the BDNF Cascade Hypothesis, neurodegeneration may originate from BDNF deficiency, which will cause miR-132 deficiency, resulting in elevated total and 4R Tau level, consequently leading to neuronal hyperexcitability. Different neurodegenerative disorders may result from distinct hyperactive neurons in specific brain regions. In the past few years, significant progress has been made in pinpointing the hyperactive neurons that lead to various neurodegenerative disorders (Figure 1). Further details are discussed in Paper 5.


Figure A-1. A model for the pathogenesis of HD, which exhibits wide variety of symptoms similar to other neurodegenerative disorders. EC: entorhinal cortex; ACC: anterior cingulate cortex; FTD: frontotemporal dementia; STN: subthalamic nucleus.


Author: Frank Lee
First published: July 20, 2015
Last updated: May 23, 2019