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ALS-linked misfolded SOD1 species have divergent impacts on mitochondria

Sarah Pickles1,2, Sabrina Semmler1,3, Helen R Broom4

  • 1Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) Université de Montréal, 900 rue Saint-Denis, Local R09.442, Montréal, QC, H2X 0A9, Canada.

Acta Neuropathologica Communications
|April 29, 2016
PubMed

Insights

Misfolded superoxide dismutase (SOD1) protein contributes to familial Amyotrophic Lateral Sclerosis (ALS). Specific antibodies reveal diverse misfolded SOD1 species associated with mitochondrial damage in the spinal cord.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Genetics

Background:

  • Familial Amyotrophic Lateral Sclerosis (ALS) is linked to mutations in superoxide dismutase (SOD1), causing protein misfolding and toxic gain of function.
  • Conformation-specific antibodies targeting misfolded SOD1 have shown therapeutic potential in preclinical models.

Purpose of the Study:

  • To characterize different species of misfolded SOD1 using conformation-restricted antibodies.
  • To investigate the association of misfolded SOD1 with spinal cord mitochondria in a SOD1(G93A) rat model.

Main Methods:

  • Utilized SOD1(G93A) rat model and various conformation-specific antibodies (AMF7-63, DSE2-3H1, A5C3, B8H10, C4F6, D3H5).
  • Examined antibody labeling patterns in spinal cord tissue, including motor neurons and mitochondria.
  • Analyzed misfolded SOD1 presence in spinal cord homogenates and isolated mitochondria, including demetalated SOD1.

Main Results:

  • Distinct antibody labeling patterns indicated different misfolded SOD1 species, including fibrillar networks and puncta in motor neurons and neuropil.
  • Time-dependent accumulation of misfolded SOD1 on spinal cord mitochondria was observed, with some antibodies correlating with mitochondrial volume changes.
  • Antibodies AMF7-63, DSE2-3H1, and B8H10 detected misfolded SOD1 aggregates in spinal cord homogenates and isolated mitochondria.
  • Demetalated SOD1 showed increased affinity for mitochondria and was recognized by antibodies B8H10 and DSE2-3H1.

Conclusions:

  • Multiple non-native, misfolded SOD1 species exist, some contributing to mitochondrial damage in ALS.
  • Conformation-specific antibodies are crucial tools for identifying and characterizing these diverse misfolded SOD1 species.
  • Understanding SOD1 species variations is vital for developing targeted SOD1-based therapeutics for ALS.
Keywords:
Amyotrophic Lateral SclerosisFlow cytometryMitochondriaSuperoxide dismutase

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