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

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.

Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

“…Kinetin, an adenosine N 6 -furfuryladenine moiety, has been found to mirror PINK1 action, increasing Parkin recruitment to damaged mitochondria; which leads to reduced apoptosis in human derived dopaminergic neurons [184] . More recently, however, an in vivo study in an alpha synuclein rodent model found no positive effect of kinetin treatment [185] .…”

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

“…Moreover, spurious activation of the PINK1/Parkin pathway in an otherwise healthy context, by arresting mitochondrial movement, may prove as deleterious as loss of the pathway when PINK1 or Parkin are mutated. This may explain why kinetin, a PINK1 activator, failed to have the beneficial effects that were hoped for in a synuclein PD rodent model (Orr et al, 2017). …”

Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease

“…[21] This suggested that the glycosylation of kinetin into kinetin riboside, rather than the first phosphorylation step, might be the rate-limiting step of the four bioconversion steps from kinetin to the active KTP.T he data from this study confirmed the initial observation of kinetin being aw eak activatoro fP INK1 in cells, and this might explain the lack of in vivo PINK1 activation when using kinetin. [15] Additionally,i ts upported our hypothesis that, for unnatural (modified) nucleobases such as kinetin, their multistep bioconversion in cells and in vivo might not be as efficient as for natural nucleobases, and this ultimately limits their pharmacological efficacy.O verall, this work highlighted that working on the nucleoside or the nucleoside monophosphate level could yield more-potent activators for PINK1 than the use of nucleobases.…”

“…Indeed, in cells treated with kinetin, KTP was detected and a degree of PINK1 activation was also observed, as judged by increased phosphorylation of the antiapoptotic protein Bcl‐xL, a PINK1 substrate . Although subsequent work showed that long‐term oral dosing of kinetin did not protect against α‐synuclein‐induced neurodegeneration in rodent models of PD, it must be noted that kinetin itself is of very low efficacy in cells …”

“…[14] Indeed, in cells treated with kinetin,KTP was detected and ad egree of PINK1 activation was also observed, as judged by increased phosphorylationo ft he antiapoptotic protein Bcl-xL, aP INK1 substrate. [14] Although subsequentw ork showed that long-term oral dosing of kinetind id not protect against asynuclein-induced neurodegeneration in rodent modelso f PD, [15] it must be noted that kinetin itself is of very low efficacy in cells. [14] We hypothesised that to generate more-potentP INK1 activators, working at the nucleoside monophosphate level, that is, kinetin riboside monophosphate (3,S cheme 1), would bypass the glycosylation and first phosphorylation steps,w hich, if they do not proceed with high efficiency in cells andi nv ivo, limit the amounts of active KTP generated.…”