Mutations in the huntingtin gene may alter the interactions between the huntingtin protein and a protein called Rac1 in the early stages of Huntington’s disease, which may affect the way nerve cells communicate, a study has found.
The study, “Rac1 Activity Is Modulated by Huntingtin and Dysregulated in Models of Huntington’s Disease,” was published in the Journal of Huntington’s Disease.
Like the skeletal system, the cytoskeleton offers structural support, helps cells move around, and enables the transport of molecules inside of cells.
Cells can change shape through the motion of motor proteins along cellular “roads” made of actin, a protein found in muscle fibers where it plays a role in muscle contraction.
Previous studies have suggested that huntingtin, the protein mutated in Huntington’s disease, “is required for actin-based changes in cell morphology,” according to the researchers.
Rac1 is known for controlling changes in the shape of cells by regulating actin cytoskeleton reorganization in response to growth molecules (also called growth factors) that act downstream of an important cellular enzyme called PI 3-kinase, which is involved in cell growth, motility, survival, and intracellular trafficking.
Investigators at Massachusetts General Hospital (MGH) in Boston investigated if Rac1 activity is impaired in Huntington’s disease patients or if it could be regulated by normal huntingtin.
Lowering the levels of normal huntingtin was found to increase Rac1 activation in healthy human skin cells (fibroblasts) and nerve cells cultured in a lab dish. However, lowering total huntingtin levels (both normal and mutant) in skin cells, neural stem cells, and neurons with a mutation in the huntingtin gene appeared to counteract an abnormal increase in Rac1 activation.
This suggests that huntingtin somehow regulates Rac1 activity.
“These data suggest that ongoing trials using huntingtin-lowering reagents may be beneficial to [Huntington’s] patients, but the same treatment might be quite toxic to normal individuals,” Kimberly Kegel-Gleason, PhD, from the department of neurology at MGH and the study’s leader, said in press release.
Using a mouse model of Huntington’s disease, scientists observed high levels of Rac1 activity in the animals’ striatum — a brain region that controls movement and is severely damaged in Huntington’s disease.
Increased Rac1 activity was also found in cultured neurons from the cortex of mouse embryo models of the disease. The cortex is a brain region that plays a key role in memory, attention, thought, and language, among other functions.
Biochemical analysis of the animals’ striatum revealed that huntingtin closely interacted with the active form of Rac1. In addition, huntingtin was found to form a molecular complex with Rac 1, a specific subunit of the PI 3-kinase and with an actin-binding protein called alpha-actinin.
Importantly, the disease-related mutation was found to reduce huntingtin’s interaction with PI 3-kinase, indicating that Rac1 activity is regulated by huntingtin following growth factor signaling.
Evidence indicates that Rac1 activity is crucial for neural development, including the formation of dendrites — nerve cell projections that are responsible for receiving signals from other neighboring nerve cells.
The shape of dendrites can influence the strength of connections between neurons and, as such, affect the entire connectivity of the neuronal network.
The team believes that an excessive activation of the Rac1 protein may lead to the formation of abnormal dendrites, a process that occurs at an early stage of the disease. This may help explain the early changes observed in Huntington’s disease, before the onset of motor symptoms.
“We are excited about this finding because it describes a functional change that occurs very early in [Huntington’s disease] models, including in human neurons, and might underlie the earliest changes experienced by [Huntington’s] patients,” Kegel-Gleason said.
“Rac1 is currently a major target of investigation in the cancer field and in Crohn’s disease, so compounds that can modify its function are already being heavily investigated. Thus, we can exploit the knowledge obtained by other clinicians and researchers to help us identify potential early interventions for [Huntington’s],” she said.
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