Geon A. The Pathogenesis of Huntington's Disease Alzheimer

Huntington's disease (HD) shares symptoms with most of other neurodegenerative disorders, such as motor dysfunction (Parkinson's disease and amyotrophic lateral sclerosis), impaired cognition (Alzheimer's disease and frontotemporal dementia) and lack of motivation (depression). It 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

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Figure A-1. A simplified schematic diagram for the pathogenesis of HD, which shares symptoms (in parenthesis) with other neurodegenerative disorders. EC: entorhinal cortex; ACC: anterior cingulate cortex; AIC: anterior insula cortex; STN: subthalamic nucleus; LC: locus coeruleus; ALS: amyotrophic lateral sclerosis; FTD: frontotemporal dementia.

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, partly due to its heavy dependence on BDNF transport (Zhao et al., 2016). Other areas impaired by HD include EC (Braak and Braak, 1992), STN (Callahan and Abercrombie, 2015), LC (Zweig et al., 1992), and cerebral cortex (Vuono et al., 2015), particularly the primary motor cortex and anterior cingulate cortex (ACC) (Thu et al., 2010). Tau pathology in each region give rise to a distinct neurodegenerative disorder (Figure 1). Further details are discussed in this research paper.

 

Author: Frank Lee
First published: July 20, 2015
Last updated: April 1, 2017