Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells

Abstract

It has long been hypothesized that abnormalities in lipid biology contribute to degenerative brain diseases. Consistent with this, emerging epidemiologic evidence links lipid alterations with Parkinson disease (PD), and disruption of lipid metabolism has been found to predispose to α-synuclein toxicity. We therefore investigated whether Parkin, an E3 ubiquitin ligase found to be defective in patients with early onset PD, regulates systemic lipid metabolism. We perturbed lipid levels by exposing Parkin +/+ and Parkin -/-mice to a high-fat and -cholesterol diet (HFD). Parkin -/-mice resisted weight gain, steatohepatitis, and insulin resistance. Introduction PARK2 mutations associate with an autosomal recessive juvenileform of Parkinson disease (PD) (1). However, the role of Parkin in the development of PD in mice is surprisingly modest, as the genetic deletion of Parkin (2, 3) and the combined KO of Parkin with additional "candidate Parkinson susceptibility genes" PINK1 and DJ-1 do not substantially replicate the human condition (4). These unexpected findings suggest that the biological function of Parkin may not primarily modulate neurodegeneration but rather that PARK2 mutations increase biological susceptibility to stressors that manifest with substantia nigra neurodegeneration. Thus, the characterization of the functional actions of Parkin could be instrumental in delineating its role in the pathophysiology underpinning the development of PD.Parkin encodes an E3 ubiquitin protein ligase and contains 465 amino acids with multiple distinct domains, including a ubiquitinlike domain, a unique Parkin-specific domain, 2 RING domains, and an in-between-RING domain (5). The structure of this protein with its multiple binding domains is most likely central to the myriad of functions prescribed to Parkin (6). Additionally, the subcellular location of Parkin appears to be dynamic, with a predominant cytosolic localization with redistribution to the nucleus (7) and to the outer mitochondrial membrane (8, 9). Parkin exhibits mono- and multiubiquitination functions (10), and studies show that classical as well as nonclassical ubiquitin linkages facilitate proteosome-dependent and independent Parkin effects (11)(12)(13)(14).

Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling

“…D, mitochondrial morphology was analyzed in non-transfected and Parkin-shRNA expressing primary neurons. Cells were treated with DMSO or 2 nM rotenone for 18 h. Knockdown efficiency of the Parkin-shRNA has been confirmed previously (45). E, mitochondrial morphology was analyzed in cKD and PARKIN KD M17 cells treated with DMSO control, CCCP (100 nM), rotenone (200 nM) or H 2 O 2 (100 nM).…”

Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43

“…8C). A reduction of CD36 and thus a correlation with fat metabolism has been recently reported from Parkin mutant animals (59). Whether the relative reduction of Parkin detectable in hTDP-43 A315T animals (Fig.…”

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy

“…Moreover, the regulation of FBXW7 by Parkin suggests a putative feedback loop providing regulatory countermeasures. Although further work will be required to elucidate these mechanisms, additional evidence supports a role for Parkin in regulating lipid metabolism; Parkin has been reported to ubiquitinate and stabilize both the SREBP target FASN and the fatty acid transporter CD36 (9,28). Finally, the identification of SREBF1 as a GWAS risk locus for sporadic PD (10), coupled with our findings that this pathway regulates mitophagy, provides further support that the causes of sporadic and autosomal recessive PD may share some mechanistic overlap.…”