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

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

Author information

1
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, USA. Electronic address: klandrock@tamu.edu.
2
Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. Electronic address: psullivian@ninds.nih.gov.
3
Interdepartmental Program of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. Electronic address: martinis@bcm.edu.
4
Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. Electronic address: goldsteind@ninds.nih.gov.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA. Electronic address: bgraham@bcm.edu.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA. Electronic address: yamamoto@bcm.edu.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA. Electronic address: hbellen@bcm.edu.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA. Electronic address: rgibbs@bcm.edu.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA. Electronic address: rchen@bcm.edu.
10
University Campus Bio-Medico, Department of Medicine, Unit of Molecular Neurosciences, Rome, Italy. Electronic address: m.damelio@hsantalucia.it.
11
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, USA. Electronic address: gstoica@cvm.tamu.edu.

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.

KEYWORDS:

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

PMID:
29217155
DOI:
10.1016/j.brainres.2017.11.029
[Indexed for MEDLINE]

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