Format

Send to

Choose Destination
Prog Neurobiol. 2019 Oct 24:101718. doi: 10.1016/j.pneurobio.2019.101718. [Epub ahead of print]

Neurofilament-lysosomal genetic intersections in the cortical network of stuttering.

Author information

1
Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; University of Navarra School of Medicine, University of Navarra, Pamplona, Navarra, Spain.
2
Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; University of Exeter, Exeter, England, UK.
3
Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Neurotechnology Laboratory, Tecnalia Health Department, Tecnalia, Derio, Basque Country, Spain.
4
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
5
Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
6
Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Neuropsychology and Functional Neuroimaging Group, Department of Basic Psychology, Universitat Jaume I, Castellón, Spain.
7
Department of Psychiatry, University of Michigan, Michigan, USA; Katzin Diagnostic and Research PET/MRI Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
8
Department of Psychiatry, University of Michigan, Michigan, USA; Cognitive Imaging Research Center, Department of Radiology, Michigan State University, East Lansing, MI, USA.
9
Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. Electronic address: sepulcre@nmr.mgh.harvard.edu.

Abstract

The neurobiological underpinnings of stuttering, a speech disorder characterized by disrupted speech fluency, remain unclear. While recent developments in the field have afforded researchers the ability to pinpoint several genetic profiles associated with stuttering, how these specific genetic backgrounds impact neuronal circuits and how they generate or facilitate the emergence of stuttered speech remains unknown. In this study, we identified the large-scale cortical network that characterizes stuttering using functional connectivity MRI and graph theory. We performed a spatial similarity analysis that examines whether the topology of the stuttering cortical network intersects with genetic expression levels of previously reported genes for stuttering from the protein-coding transcriptome data of the Allen Human Brain Atlas. We found that GNPTG - a gene involved in the mannose-6-phosphate lysosomal targeting pathways - was significantly co-localized with the stuttering cortical network. An enrichment analysis demonstrated that the genes identified with the stuttering cortical network shared a significantly overrepresented biological functionality of Neurofilament Cytoskeleton Organization (NEFH, NEFL and INA). The relationship between lysosomal pathways, cytoskeleton organization, and stuttering, was investigated by comparing the genetic interactome between GNPTG and the neurofilament genes implicated in the current study. We found that genes of the interactome network, including CDK5, SNCA, and ACTB, act as functional links between lysosomal and neurofilament genes. These findings support the notion that stuttering is due to a lysosomal dysfunction, which has deleterious effects on the neurofilament organization of the speech neuronal circuits. They help to elucidate the intriguing, unsolved link between lysosomal mutations and the presence of stuttering.

KEYWORDS:

Cortical network; Genetics; Lysosomal; Neurofilament; Stuttering

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center