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Neurochem Int. 2017 Oct;109:106-116. doi: 10.1016/j.neuint.2017.04.006. Epub 2017 Apr 20.

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease.

Author information

1
Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
2
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
3
Mitokinin LLC, 2 Wall Street, 4th Floor, New York, NY, USA.
4
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
5
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Mitokinin LLC, 2 Wall Street, 4th Floor, New York, NY, USA.
6
Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: ken.nakamura@gladstone.ucsf.edu.

Abstract

Mutations in the mitochondrial kinase PTEN-induced putative kinase 1 (PINK1) cause Parkinson's disease (PD), likely by disrupting PINK1's kinase activity. Although the mechanism(s) underlying how this loss of activity causes degeneration remains unclear, increasing PINK1 activity may therapeutically benefit some forms of PD. However, we must first learn whether restoring PINK1 function prevents degeneration in patients harboring PINK1 mutations, or whether boosting PINK1 function can offer protection in more common causes of PD. To test these hypotheses in preclinical rodent models of PD, we used kinetin triphosphate, a small-molecule that activates both wild-type and mutant forms of PINK1, which affects mitochondrial function and protects neural cells in culture. We chronically fed kinetin, the precursor of kinetin triphosphate, to PINK1-null rats in which PINK1 was reintroduced into their midbrain, and also to rodent models overexpressing α-synuclein. The highest tolerated dose of oral kinetin increased brain levels of kinetin for up to 6 months, without adversely affecting the survival of nigrostriatal dopamine neurons. However, there was no degeneration of midbrain dopamine neurons lacking PINK1, which precluded an assessment of neuroprotection and raised questions about the robustness of the PINK1 KO rat model of PD. In two rodent models of α-synuclein-induced toxicity, boosting PINK1 activity with oral kinetin provided no protective effects. Our results suggest that oral kinetin is unlikely to protect against α-synuclein toxicity, and thus fail to provide evidence that kinetin will protect in sporadic models of PD. Kinetin may protect in cases of PINK1 deficiency, but this possibility requires a more robust PINK1 KO model that can be validated by proof-of-principle genetic correction in adult animals.

KEYWORDS:

AAV; Adeno-associated virus; Kinetin; Neurodegeneration; PINK1; Parkinson's disease; α-Synuclein

PMID:
28434973
PMCID:
PMC5641232
DOI:
10.1016/j.neuint.2017.04.006
[Indexed for MEDLINE]
Free PMC Article

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