Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson’s Disease

Abstract

Parkin and α-synuclein are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Neurotoxic alterations of α-synuclein that lead to the formation of toxic oligomers and fibrils contribute to PD through synaptic dysfunction, mitochondrial impairment, defective endoplasmic reticulum and Golgi function, and nuclear dysfunction. In half of the cases, the recessively inherited early-onset PD is caused by loss of function mutations in the PARK2 gene that encodes the E3-ubiquitin ligase, parkin. Parkin is involved in the clearance of misfolded and aggregated proteins by the ubiquitin-proteasome system and regulates mitophagy and mitochondrial biogenesis. PARK2-related PD is generally thought not to be associated with Lewy body formation although it is a neuropathological hallmark of PD. In this review article, we provide an overview of post-mortem neuropathological examinations of PARK2 patients and present the current knowledge of a functional interaction between parkin and α-synuclein in the regulation of protein aggregates including Lewy bodies. Furthermore, we describe prevailing hypotheses about the formation of intracellular micro-aggregates (synuclein inclusions) that might be more likely than Lewy bodies to occur in PARK2-related PD. This information may inform future studies aiming to unveil primary signaling processes involved in PD and related neurodegenerative disorders.

Parkinson's Disease Modification Through Abl Kinase Inhibition: An Opportunity

“…[32][33][34][35][36][37][38][63][64][65][66][67][68][69][70][71][72] C-Abl also inactivates parkin by chemical modification, which affects mitochondrial quality control and suppresses protein clearance mechanisms. [28][29][30][31][32][33][34][77][78][79] Parkin inactivation suppresses the complex interplay between parkin and pink1 at the mitochondrion, which act in concert to maintain mitochondrial integrity, quality and regulate mitochondrial biogenesis. 77 Parkin inactivation leads to the accumulation of toxic parkin substrates, such as the parkin interacting substrate (PARIS), the aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) and the far upstream element-binding protein 1 (FBP1).…”

“…77 Parkin inactivation leads to the accumulation of toxic parkin substrates, such as the parkin interacting substrate (PARIS), the aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) and the far upstream element-binding protein 1 (FBP1). [28][29][30][31][32][33][34][77][78][79] PARIS and AIMP2 accumulate in adult conditional parkin knockout mice and MPTPintoxicated mice as well as in patients with PD. Increased levels of PARIS can lead to mitochondrial dysfunction through downregulation of the peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α transcriptional co-activator protein and loss of DA neurons in a PARIS-dependent manner.…”

“…Chemical modification creates a form of α‐synuclein that represents the pathologic species of the disease leading to disruption of mitochondrial integrity, negatively impact the endosome, disrupt nucleosomal structure and modulate transcription of certain genes 32‐38,63‐72 . C‐Abl also inactivates parkin by chemical modification, which affects mitochondrial quality control and suppresses protein clearance mechanisms 28‐34,77‐79 . Parkin inactivation suppresses the complex interplay between parkin and pink1 at the mitochondrion, which act in concert to maintain mitochondrial integrity, quality and regulate mitochondrial biogenesis 77 .…”

“…Parkin inactivation suppresses the complex interplay between parkin and pink1 at the mitochondrion, which act in concert to maintain mitochondrial integrity, quality and regulate mitochondrial biogenesis 77. Parkin inactivation leads to the accumulation of toxic parkin substrates, such as the parkin interacting substrate (PARIS), the aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) and the far upstream element-binding protein 1 (FBP1) [28][29][30][31][32][33][34][77][78][79]. PARIS and AIMP2 accumulate in adult conditional parkin knockout mice and MPTPintoxicated mice as well as in patients with PD.…”

The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson’s Disease

“…Parkin activates phosphatase A2, which in turn de-phosphorylates α-syn, thus attenuating cell death and inflammation. Conversely, α-syn counteracts this molecular pathway, enhancing cell loss [ 30 ].…”