Pleiotropic neuropathological and biochemical alterations associated with Myo5a mutation in a rat Model

Brain Res. 2018 Jan 15;1679:155-170. doi: 10.1016/j.brainres.2017.11.029. Epub 2017 Dec 5.


In this study, we analyze the neuropathological and biochemical alterations involved in the pathogenesis of a neurodegenerative/movement disorder during different developmental stages in juvenile rats with a mutant Myosin5a (Myo5a). In mutant rats, a spontaneous autosomal recessive mutation characterized by the absence of Myo5a protein expression in the brain is associated with a syndrome of locomotor dysfunction, altered coat color, and neuroendocrine abnormalities. Myo5a encodes a myosin motor protein required for transport and proper distribution of subcellular organelles in somatodendritic processes in neurons. Here we report marked hyperphosphorylation of alpha-synuclein and tau, as well as region-specific buildup of the autotoxic dopamine metabolite, 3,4-dihydroxyphenyl-acetaldehyde (DOPAL), related to decreased aldehyde dehydrogenases activity and neurodegeneration in mutant rats. Alpha-synuclein accumulation in mitochondria of dopaminergic neurons is associated with impaired enzymatic respiratory complex I and IV activity. The behavioral and biochemical lesions progress after 15 days postnatal, and by 30-40 days the animals must be euthanized because of neurological impairment. Based on the obtained results, we propose a pleiotropic pathogenesis that links the Myo5a gene mutation to deficient neuronal development and progressive neurodegeneration. This potential model of a neurodevelopmental disorder with neurodegeneration and motor deficits may provide further insight into molecular motors and their associated proteins responsible for altered neurogenesis and neuronal disease pathogenesis.

Keywords: Autophagy; Dopamine metabolism alteration; Dying back neurodegeneration; Mitochondria complex I-IV; Myo5a mutation; TEM; α-synuclein/tau-P.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / analogs & derivatives
  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Animals
  • Central Nervous System / metabolism*
  • Central Nervous System / pathology*
  • Central Nervous System / ultrastructure
  • Disease Models, Animal
  • Electron Transport Chain Complex Proteins / metabolism
  • Heredodegenerative Disorders, Nervous System* / genetics
  • Heredodegenerative Disorders, Nervous System* / metabolism
  • Heredodegenerative Disorders, Nervous System* / pathology
  • Microscopy, Electron, Transmission
  • Mutation / genetics*
  • Myosin Heavy Chains / genetics*
  • Myosin Heavy Chains / metabolism
  • Myosin Type V / genetics*
  • Myosin Type V / metabolism
  • Phosphorylation / genetics
  • Rats
  • Rats, Mutant Strains
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism
  • alpha-Synuclein / ultrastructure
  • tau Proteins / genetics
  • tau Proteins / metabolism*
  • tau Proteins / ultrastructure


  • Electron Transport Chain Complex Proteins
  • Myo5a protein, rat
  • alpha-Synuclein
  • tau Proteins
  • 3,4-Dihydroxyphenylacetic Acid
  • 3,4-dihydroxyphenylacetaldehyde
  • Myosin Type V
  • Myosin Heavy Chains