RGD Reference Report - Pleiotropic neuropathological and biochemical alterations associated with Myo5a mutation in a rat Model. - Rat Genome Database

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

Authors: Landrock, Kerstin K  Sullivan, Patti  Martini-Stoica, Heidi  Goldstein, David S  Graham, Brett H  Yamamoto, Shinya  Bellen, Hugo J  Gibbs, Richard A  Chen, Rui  D'Amelio, Marcello  Stoica, George 
Citation: Landrock KK, etal., Brain Res. 2018 Jan 15;1679:155-170. doi: 10.1016/j.brainres.2017.11.029. Epub 2017 Dec 5.
RGD ID: 42721980
Pubmed: PMID:29217155   (View Abstract at PubMed)
PMCID: PMC7696654   (View Article at PubMed Central)
DOI: DOI:10.1016/j.brainres.2017.11.029   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
synucleinopathy  IAGP 42721980compared to control BD-IVRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
dopamine metabolic process  IMP 42721980 RGD 
macroautophagy  IMP 42721980 RGD 
positive regulation of cytochrome-c oxidase activity  IMP 42721980 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal autophagosome formation  IAGP 42721980compared to control BD-IVRGD 
abnormal dorsal striatum morphology  IAGP 42721980compared to control BD-IVRGD 
abnormal mitochondrial ATP synthesis coupled electron transport  IAGP 42721980compared to control BD-IVRGD 
abnormal olfactory tract morphology  IAGP 42721980 RGD 
abnormal Purkinje cell dendrite morphology  IAGP 42721980compared to control BD-IVRGD 
abnormal substantia nigra pars compacta morphology  IAGP 42721980compared to control BD-IVRGD 
alpha-synuclein inclusion body  IAGP 42721980in brain stem more ...RGD 
demyelination  IAGP 42721980in axons in striatum and compared to control BD-IVRGD 
tau protein deposits  IAGP 42721980in brain stem more ...RGD 
variegated coat color  IAGP 42721980compared to control BD-IVRGD 
Objects Annotated

Genes (Rattus norvegicus)
Myo5a  (myosin VA)

Strains
BDIV-Myo5a/StcRrrc  (NA)


Additional Information