A network biology approach to unraveling inherited axonopathies

Dana M. Bis-Brewer, Matt C. Danzi, Stefan Wuchty, Stephan L Zuchner

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Inherited axonopathies represent a spectrum of disorders unified by the common pathological mechanism of length-dependent axonal degeneration. Progressive axonal degeneration can lead to both Charcot-Marie-Tooth type 2 (CMT2) and Hereditary Spastic Paraplegia (HSP) depending on the affected neurons: peripheral motor and sensory nerves or central nervous system axons of the corticospinal tract and dorsal columns, respectively. Inherited axonopathies display an extreme degree of genetic heterogeneity of Mendelian high-penetrance genes. High locus heterogeneity is potentially advantageous to deciphering disease etiology by providing avenues to explore biological pathways in an unbiased fashion. Here, we investigate ‘gene modules’ in inherited axonopathies through a network-based analysis of the Human Integrated Protein-Protein Interaction rEference (HIPPIE) database. We demonstrate that CMT2 and HSP disease proteins are significantly more connected than randomly expected. We define these connected disease proteins as ‘proto-modules’ and show the topological relationship of these proto-modules by evaluating their overlap through a shortest-path based measurement. In particular, we observe that the CMT2 and HSP proto-modules significantly overlapped, demonstrating a shared genetic etiology. Comparison of both modules with other diseases revealed an overlapping relationship between HSP and hereditary ataxia and between CMT2 + HSP and hereditary ataxia. We then use the DIseAse Module Detection (DIAMOnD) algorithm to expand the proto-modules into comprehensive disease modules. Analysis of disease modules thus obtained reveals an enrichment of ribosomal proteins and pathways likely central to inherited axonopathy pathogenesis, including protein processing in the endoplasmic reticulum, spliceosome, and mRNA processing. Furthermore, we determine pathways specific to each axonopathy by analyzing the difference of the axonopathy modules. CMT2-specific pathways include glycolysis and gluconeogenesis-related processes, while HSP-specific pathways include processes involved in viral infection response. Unbiased characterization of inherited axonopathy disease modules will provide novel candidate disease genes, improve interpretation of candidate genes identified through patient data, and guide therapy development.

Original languageEnglish (US)
Article number1692
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Hereditary Spastic Paraplegia
Tooth
Spinocerebellar Degenerations
Proteins
Spliceosomes
Genes
Pyramidal Tracts
Gluconeogenesis
Genetic Heterogeneity
Penetrance
Gene Regulatory Networks
Ribosomal Proteins
Motor Neurons
Sensory Receptor Cells
Glycolysis
Virus Diseases
Endoplasmic Reticulum
Axons
Central Nervous System
Databases

ASJC Scopus subject areas

  • General

Cite this

A network biology approach to unraveling inherited axonopathies. / Bis-Brewer, Dana M.; Danzi, Matt C.; Wuchty, Stefan; Zuchner, Stephan L.

In: Scientific reports, Vol. 9, No. 1, 1692, 01.12.2019.

Research output: Contribution to journalArticle

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