PUBLICATION

Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function

Authors
Sztal, T.E., Zhao, M., Williams, C., Oorschot, V., Parslow, A.C., Giousoh, A., Yuen, M., Hall, T.E., Costin, A., Ramm, G., Bird, P.I., Busch-Nentwich, E.M., Stemple, D.L., Currie, P.D., Cooper, S.T., Laing, N.G., Nowak, K.J., Bryson-Richardson, R.J.
ID
ZDB-PUB-150502-3
Date
2015
Source
Acta Neuropathologica   130(3): 389-406 (Journal)
Registered Authors
Bryson-Richardson, Robert, Busch-Nentwich, Elisabeth, Currie, Peter D., Hall, Thomas, Parslow, Adam, Stemple, Derek L., Zhao, Mo
Keywords
Nemaline, Myopathy, Zebrafish, Actin, Protein aggregation
MeSH Terms
  • Actinin/genetics
  • Actinin/metabolism
  • Actins/metabolism
  • Animals
  • Animals, Genetically Modified
  • Cytoplasm/metabolism
  • Cytoplasm/pathology
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Morpholinos
  • Muscle Proteins/genetics
  • Muscle Proteins/metabolism
  • Muscle Weakness/pathology
  • Muscle Weakness/physiopathology
  • Muscle, Skeletal/pathology*
  • Muscle, Skeletal/physiopathology*
  • Mutation
  • Myopathies, Nemaline/pathology*
  • Myopathies, Nemaline/physiopathology*
  • Phenotype
  • Sarcomeres/metabolism
  • Sarcomeres/pathology
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
25931053 Full text @ Acta Neuropathol.
Abstract
Nemaline myopathy is characterized by muscle weakness and the presence of rod-like (nemaline) bodies. The genetic etiology of nemaline myopathy is becoming increasingly understood with mutations in ten genes now known to cause the disease. Despite this, the mechanism by which skeletal muscle weakness occurs remains elusive, with previous studies showing no correlation between the frequency of nemaline bodies and disease severity. To investigate the formation of nemaline bodies and their role in pathogenesis, we generated overexpression and loss-of-function zebrafish models for skeletal muscle α-actin (ACTA1) and nebulin (NEB). We identify three distinct types of nemaline bodies and visualize their formation in vivo, demonstrating these nemaline bodies not only exhibit different subcellular origins, but also have distinct pathological consequences within the skeletal muscle. One subtype is highly dynamic and upon breakdown leads to the accumulation of cytoplasmic actin contributing to muscle weakness. Examination of a Neb-deficient model suggests this mechanism may be common in nemaline myopathy. Another subtype results from a reduction of actin and forms a more stable cytoplasmic body. In contrast, the final type originates at the Z-disk and is associated with myofibrillar disorganization. Analysis of zebrafish and muscle biopsies from ACTA1 nemaline myopathy patients demonstrates that nemaline bodies also possess a different protein signature. In addition, we show that the ACTA1(D286G) mutation causes impaired actin incorporation and localization in the sarcomere. Together these data provide a novel examination of nemaline body origins and dynamics in vivo and identifies pathological changes that correlate with muscle weakness.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes