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

ABSTRACT: 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.

SUBMITTER: Landrock KK

PROVIDER: S-EPMC7696654 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Landrock Kerstin K KK Sullivan Patti P Martini-Stoica Heidi H Goldstein David S DS Graham Brett H BH Yamamoto Shinya S Bellen Hugo J HJ Gibbs Richard A RA Chen Rui R D'Amelio Marcello M Stoica George G

Brain research 20171205

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 ...[more]

PMID: 29217155

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

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

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