Rescue of Pink1 Deficiency by Stress-Dependent Activation of Autophagy

Abstract

Stimulating autophagy is a promising therapeutic strategy for slowing the progression of neurodegenerative disease. Neurons are insensitive to current approaches based on mTOR inhibition for activating autophagy, and instead may rely on the Parkinson's disease-associated proteins PINK1 and PARKIN to activate the autophagy-lysosomal pathway in response to mitochondrial damage. We developed a multifactorial zebrafish drug-screening platform combining Pink1 deficiency with an environmental toxin to compromise mitochondrial function and trigger dopaminergic neuron loss. Using a phenotypic screening strategy, we identified a series of piperazine phenothiazines, including trifluoperazine, which rescued Pink1 deficiency by activating autophagy selectively in stressed zebrafish and human cells. We show that trifluoperazine acts downstream of, or parallel to, PINK1/PARKIN to stimulate transcription factor EB nuclear translocation and the expression of autophagy-lysosomal target genes. These data suggest that stress-dependent pharmacological reactivation of autophagy could prevent the loss of vulnerable neurons to slow neurodegeneration.

PINK1-Based Screen Shines Light on Autophagy Enhancers for Parkinson’s Disease

“…In this case, however, Zhang et al (2017) show that TFP induces autophagy by activating transcription factor EB (TFEB) and its target gene SQSTM1 independent of PINK1 and Parkin, presumably indicating that the pathway acts in parallel or downstream of PINK1 and Parkin. Interestingly, increased autophagy through this PINK1-independent mechanism also appears to underlie the improved mitochondrial function, as the improvement in a range of bioenergetic parameters is blocked by bafilomycin.…”

“… In this issue of Cell Chemical Biology , Zhang et al (2017) report a zebrafish model of Parkinson’s disease (PD), incorporating the PD-protein PINK1 and rotenone, a toxin linked to PD. Using it as a drug-screening platform, they identify trifluoperazine and other piperazine phenothiazines as protective compounds that enhance autophagy independent of PINK1.…”

“…In this issue of Cell Chemical Biology , Zhang et al (2017) add an important new resource for researchers. They report an elegant model for PINK1 deficiency in zebrafish based on the presence of a touch-evoked escape response.…”

“…Zhang et al (2017) use their model system to screen 727 small-molecule compounds, identifying three structurally related piperazine phenothiazines (i.e., trifluoperazine [TFP], fluphenazine [FLU], and prochlorperazine [PRO]) as the only hits that normalized their behavioral screen, improved mitochondrial function and blocked DA neuron death. Furthermore, they found these compounds increase autophagy, consistent with prior reports (Tsvetkov et al, 2010), while inhibiting autophagy abrogates the protective effects.…”

“…Overall, Zhang et al (2017) establish a robust model system that complements existing approaches and may be a valuable platform for screening therapeutic compounds. In particular, combining genetic and environmental risk factors is an important step and likely necessary to accurately model neurodegenerative diseases, such as PD, that are heterogeneous and primarily sporadic.…”