Parkin Promotes Degradation of the Mitochondrial Pro-Apoptotic ARTS Protein

Abstract

Parkinson’s disease (PD) is associated with excessive cell death causing selective loss of dopaminergic neurons. Dysfunction of the Ubiquitin Proteasome System (UPS) is associated with the pathophysiology of PD. Mutations in Parkin which impair its E3-ligase activity play a major role in the pathogenesis of inherited PD. ARTS (Sept4_i2) is a mitochondrial protein, which initiates caspase activation upstream of cytochrome c release in the mitochondrial apoptotic pathway. Here we show that Parkin serves as an E3-ubiquitin ligase to restrict the levels of ARTS through UPS-mediated degradation. Though Parkin binds equally to ARTS and Sept4_i1 (H5/PNUTL2), the non-apoptotic splice variant of Sept4 , Parkin ubiquitinates and degrades only ARTS. Thus, the effect of Parkin on ARTS is specific and probably related to its pro-apoptotic function. High levels of ARTS are sufficient to promote apoptosis in cultured neuronal cells, and rat brains treated with 6-OHDA reveal high levels of ARTS. However, over-expression of Parkin can protect cells from ARTS-induced apoptosis. Furthermore, Parkin loss-of-function experiments reveal that reduction of Parkin causes increased levels of ARTS and apoptosis. We propose that in brain cells in which the E3-ligase activity of Parkin is compromised, ARTS levels increase and facilitate apoptosis. Thus, ARTS is a novel substrate of Parkin. These observations link Parkin directly to a pro-apoptotic protein and reveal a novel connection between Parkin, apoptosis, and PD.

Profiling of Parkin-Binding Partners Using Tandem Affinity Purification

“…Parkin expression has been reported to protect cells against multiple forms of stress [42] , but although the exact mechanism of this prosurvival function remains elusive, accumulating evidence exists that it involves inhibition of programmed cell death (apoptosis). Two recent studies identified Bax and the mitochondrial pro-apoptotic protein ARTS as Parkin substrates that both might contribute to the anti-apoptotic effect of Parkin [43] , [44] . In our study, we identified novel associations between Parkin and several proteins involved in cell death processes.…”

Parkinson's disease: acid‐glucocerebrosidase activity and alpha‐synuclein clearance

“…) and apoptosis‐related protein in the TGF‐beta signaling pathway (Kemeny et al . ; Bendikov‐Bar et al . ), which is deleterious to DA neurons (Imai et al .…”

“…This is proposed to correlate with disease severity, since it was found to be most extensive for the L444P mutant, which is associated with GD type III in homozygosity (Bendikov-Bar et al 2011). A direct link between mutated GC induced ERAD and PD is provided by only one study demonstrating that expression of mutant L444P impairs parkin (Park2)-mediated ERAD of unfolded proteins (Ron et al 2010) interfering with the proteasomal degradation of parkin substrates such as parkin interacting substrate (Shin et al 2011;Bendikov-Bar et al 2014;Stevens et al 2015) and apoptosis-related protein in the TGF-beta signaling pathway (Kemeny et al 2012;Bendikov-Bar et al 2014), which is deleterious to DA neurons (Imai et al 2000;Shimura et al 2000;Ron et al 2010). How mutated GC affects ERAD and a-SN degradation remains elusive and clearly requires further experimental evidence and exploration.…”

New Directions in Gaucher Disease

“…Overexpression of AIMP2 in the mouse at levels seen in PD leads to an age‐dependent degeneration of dopaminergic neurons and impairment of motoric skills. Other parkin substrates are PARIS (PARis Interacting Substrate) [Shin et al., ] and ARTS (apoptosis‐related protein in TGF beta signaling pathway, a spliced variant of SEPT4 , [NM_080415.3, NP_536340.1]) [Kemeny et al., ]. PARIS is a cytoplasmic protein whose degradation is regulated by parkin‐mediated ubiquitination.…”