Huntington disease (HD) is a neurodegenerative disorder caused by a mutation in Huntingtin (HTT) protein. The mutation determines a high number of repeats of the aminoacid glutamine in the protein. The abnormal mutant HTT accumulates in neurons, forming aggregates. Although the mechanism leading to the formation of HTT aggregates and subsequent neuronal death is not clear, several hypotheses have been made.
What about the physiological role of the HTT protein?
Mice lacking this gene die very early during embryonic development, suggesting a key role of this protein in cell physiology.
Although patients affected by HD show the typical symptoms of the disease starting from 30-50 years of age (the disease onset depends on the number of repeats of glutamine caused by the mutation), people carrying mutation of HTT have smaller brain volumes compared to control, even before the disease onset, and children at risk of developing HD have smaller heads. This suggested the hypothesis of a physiological role of HTT in brain development, and led to analyze more specifically the consequences of a mutated HTT during development.
During the embryonic stage of brain development, cells of the cortex (a region of the brain involved in higher cognitive processes) are born from a pool of neural stem cells. They divide massively in order to provide the right number of cortical cells required for a correct brain development. Firstly, these cells divide by symmetric division, then, at some point during development, they switch from a symmetric division to an asymmetric, which means that each cell produces a cell that will keep duplicating and a cell that will move away and differentiate.
How is HTT involved in this process?
Before the cells are ready to undergo division, they need to assemble a structure called “spindle”. The spindle is like a net, anchored to the borders of the cell, and is essential because it arranges the chromosomes in the right position for cell division. The filaments of the “net” are made of “wires” called microtubules. One of the typical features of microtubules is their dynamicity: they continuously polymerize and depolymerize (which means that they continuously assemble and dissemble) according to the cell needs. When the dynamicity of a microtubule is perturbed, the cell behavior is affected and, as a consequence, the correct functionality of the cell.
Right before division, the cell synthesizes the microtubules in order to assemble the spindle. Microtubules “grow” until they touch the cell membrane, then they start depolymerizing. However, in cells expressing mutant HTT protein, microtubules do not depolymerize after touching the cell membrane, but they keep polymerizing. Therefore, the dynamicity of microtubules is affected, showing a role of HTT in modulating the dynamicity of the microtubules that make up the spindle.
Moreover, several proteins are required for a correct assembling and positioning of the spindle. Among these, the dynein-dynactin complex and NuMa. All these proteins are correctly positioned by HTT. Mutated HTT affects the distribution of these proteins and, as a consequence, alters the orientation of the spindle, ultimately affecting cell division and cortical development.
In vivo, the cells display the same defects in spindle orientation, affecting brain development: the thickness of some areas of the cortex were different in mutants compared to controls, reflecting an altered cell division. This defect is retained also in adulthood.
Can we interfere with this process and correct it?
It was previously shown that the defects associated with mutant HTT can be in some cases (eg HTT is involved also in vesicular transport) corrected by phosphorylating (adding a phosphate group) HTT on a specific residue of the protein. In this case, by inducing the phosphorylation of this residue, the spindle orientation is partially rescued, both in vitro and in vivo.
Correcting the spindle orientation rescues the thickness of the cortex? We don’t know, but it would be interesting to know. So far it is not clear if in HD the neurodegeneration due to intraneuronal inclusions of mutant HTT is due to a loss of function of the protein or an acquired toxic function of the mutated. In the latter case, maybe inducing the phosphorylation might be useful not only to support a correct brain development (we don’t know if this results into altered cognitive functions already during childhood), but also to contrast the neurodegeneration induced by mutant HTT.
References: Maria Molina-Calavita et al. Mutant Huntingtin affects cortical progenitor cell division and development of the mouse neocortex. The Journal of Neuroscience, 2014.