Aging accelerates locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE
    • Publication Information:
      Publication: Orlando Fl : Academic Press
      Original Publication: New York.
    • Subject Terms:
      Tyrosine 3-Monooxygenase*/metabolism ; Protein Kinases*/genetics ; Protein Kinases*/deficiency ; Protein Kinases*/metabolism ; Substantia Nigra*/metabolism ; Aging*/genetics ; Dopamine*/metabolism ; Corpus Striatum*/metabolism; Animals ; Male ; Rats ; Motor Activity/physiology ; Motor Activity/genetics ; Rats, Transgenic
    • Abstract:
      Parkinson's disease (PD) rodent models provide insight into the relationship between nigrostriatal dopamine (DA) signaling and locomotor function. Although toxin-based rat models produce frank nigrostriatal neuron loss and eventual motor decline characteristic of PD, the rapid nature of neuronal loss may not adequately translate premotor traits, such as cognitive decline. Unfortunately, rodent genetic PD models, like the Pink1 knockout (KO) rat, often fail to replicate the differential severity of striatal DA and tyrosine hydroxylase (TH) loss, and a bradykinetic phenotype, reminiscent of human PD. To elucidate this inconsistency, we evaluated aging as a progression factor in the timing of motor and non-motor cognitive impairments. Male PINK1 KO and age-matched wild type (WT) rats were evaluated in a longitudinal study from 3 to 16 months old in one cohort, and in a cross-sectional study of young adult (6-7 months) and aged (18-19 months) in another cohort. Young adult PINK1 KO rats exhibited hyperkinetic behavior associated with elevated DA and TH in the substantia nigra (SN), which decreased therein, but not striatum, in the aged KO rats. Additionally, norepinephrine levels decreased in aged KO rats in the prefrontal cortex (PFC), paired with a higher DA levels in young and aged KO. Although a younger age of onset characterizes familial forms of PD, our results underscore the critical need to consider age-related factors. Moreover, the results indicate that compensatory mechanisms may exist to preserve locomotor function, evidenced by increased DA in the SN early in the lifespan, in response to deficient PINK1 function, which declines with aging and the onset of motor decline.
      Competing Interests: Declaration of competing interest None.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
    • Comments:
      Update of: bioRxiv. 2024 Feb 04;:. (PMID: 38352365)
    • Contributed Indexing:
      Keywords: Aging; Animal models; Mitochondria; PINK1; Parkinson's disease; Substantia nigra
    • Accession Number:
      EC 2.7.11.1 (PTEN-induced putative kinase)
      EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
      EC 2.7.- (Protein Kinases)
      VTD58H1Z2X (Dopamine)
    • Publication Date:
      Date Created: 20240405 Date Completed: 20240428 Latest Revision: 20240516
    • Publication Date:
      20240516
    • Accession Number:
      10.1016/j.expneurol.2024.114771
    • Accession Number:
      38580154