Faculty Articles

Evidence of Neurobiological Changes in the Presymptomatic PINK1 Knockout Rat.

Publication Title

J Parkinsons Dis

Publisher

I O S Press

ISSN

1877-718X

Publication Date

1-1-2018

Keywords

Adenosine Triphosphate, Animals, Brain, DNA Methylation, Disease Models, Animal, Glutathione, Learning, Magnetic Resonance Imaging, Male, Maze Learning, Motor Activity, Oxidative Stress, Parkinson Disease, Protein Kinases, Rats, Rats, Long-Evans, Rats, Transgenic, Recognition (Psychology)

Abstract

BACKGROUND: Genetic models of Parkinson's disease (PD) coupled with advanced imaging techniques can elucidate neurobiological disease progression, and can help identify early biomarkers before clinical signs emerge. PTEN-induced putative kinase 1 (PINK1) helps protect neurons from mitochondrial dysfunction, and a mutation in the associated gene is a risk factor for recessive familial PD. The PINK1 knockout (KO) rat is a novel model for familial PD that has not been neuroradiologically characterized for alterations in brain structure/function, alongside behavior, prior to 4 months of age.

OBJECTIVE: To identify biomarkers of presymptomatic PD in the PINK1 -/- rat at 3 months using magnetic resonance imaging techniques.

METHODS: At postnatal weeks 12-13; one month earlier than previously reported signs of motor and cognitive dysfunction, this study combined imaging modalities, including assessment of quantitative anisotropy across 171 individual brain areas using an annotated MRI rat brain atlas to identify sites of gray matter alteration between wild-type and PINK1 -/- rats.

RESULTS: The olfactory system, hypothalamus, thalamus, nucleus accumbens, and cerebellum showed differences in anisotropy between experimental groups. Molecular analyses revealed reduced levels of glutathione, ATP, and elevated oxidative stress in the substantia nigra, striatum and deep cerebellar nuclei. Mitochondrial genes encoding proteins in Complex IV, along with mRNA levels associated with mitochondrial function and genes involved in glutathione synthesis were reduced. Differences in brain structure did not align with any cognitive or motor impairment.

CONCLUSIONS: These data reveal early markers, and highlight novel brain regions involved in the pathology of PD in the PINK1 -/- rat before behavioral dysfunction occurs.

Volume

8

Issue

2

First Page

281

Last Page

301

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

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