Abstract
Both Neurofibromatosis type I (NF1) and inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) are autosomal dominant genetic disorders. These two diseases are fully penetrant but with high heterogeneity in phenotypes, suggesting the involvement of genetic modifiers in modulating patients' phenotypes. Although NF1 is recognized as a developmental disorder and IBMPFD is associated with degeneration of multiple tissues, a recent study discovered the direct protein interaction between neurofibromin, the protein product of the NF1 gene, and VCP/p97, encoded by the causative gene of IBMPFD. Both NF1 and VCP/p97 are critical for dendritic spine formation, which provides the cellular mechanism explaining the cognitive deficits and dementia found in patients. Moreover, disruption of the interaction between neurofibromin and VCP impairs dendritic spinogenesis. Neurofibromin likely influences multiple downstream pathways to control dendritic spinogenesis. One is to activate the protein kinase A pathway to initiate dendritic spine formation; another is to regulate the synaptic distribution of VCP and control the activity of VCP in dendritic spinogenesis. Since neurofibromin and VCP/p97 also regulate cell growth and bone metabolism, the understanding of neurofibromin and VCP/p97 in neurons may be applied to study of cancer and bone. Statin treatment rescues the spine defects caused by VCP deficiency, suggesting the potential role of statin in clinical treatment for these two diseases.
Highlights
Both Neurofibromatosis type I (NF1) and inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) are autosomal dominant genetic disorders
Both neurofibromin and valosin-containing protein (VCP)/p97 are ubiquitously expressed in many tissues and are involved in tumorigenesis [9,10,11] and bone metabolism [12,13], the current review focuses on the molecular functions of neurofibromin and VCP/p97 in neurons
Based on the symptoms identified in patients with Neurofibromatosis Type I (NF1), it is clear that the NF1 gene plays important roles in cell growth, pigmentation, neuronal activity and function, and bone metabolism
Summary
The heterogeneity of patients’ phenotypes presents an obstacle to establishing effective and specific clinical treatments for NF1 and IBMPFD. Understanding the molecular mechanisms of the pathogenesis of NF1 and IBMPFD, which still need more investigation to elucidate the finer details, is essential for overcoming these obstacles. Identification of the interacting molecules and elucidation of the crosstalk between or among the interacting proteins are certainly important to understanding the pathogenic mechanisms. The connection of the interaction between neurofibromin and VCP and the regulation of dendritic spinogenesis has provided the first molecular evidence that VCP functions as a genetic modifier for NF1. Studies in mouse genetic models and patients have to be performed to confirm the role of VCP as a downstream effector of neurofibromin. Abbreviations AAA ATPase: ATPases Associated with a variety of cellular Activities APTase; ALS: amyotrophic lateral sclerosis; CRMP: collapsing response mediator protein; CTD: C-terminal domain; Ena/VASP: Enabled/vasodilator-stimulated phosphoprotein; ERAD: endoplasmic reticulum-associated protein degradation; FTD: frontotemporal dementia; GRD: RasGAP-related domain; IBMPFD: Inclusion body myopathy with Paget disease of the bone and frontotemporal dementia; HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A; LRD: Leucine-rich domain; NF1: Neurofibromatosis Type I; TDP-43: TAR DNA binding protein 43; VCP: Valosin-containing protein
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