Showing papers by "Jin-Sung Park published in 2014"
TL;DR: It is proposed ATP13A2's modulation of zinc levels in MVBs can regulate the biogenesis of exosomes capable of containing α-Synuclein, the first PD-associated gene involved in exosome biogenesis and indicates a potential neuroprotective role ofExosomes in PD.
Abstract: α-Synuclein plays a central causative role in Parkinson's disease (PD). Increased expression of the P-type ATPase ion pump PARK9/ATP13A2 suppresses α-Synuclein toxicity in primary neurons. Our data indicate that ATP13A2 encodes a zinc pump; neurospheres from a compound heterozygous ATP13A2(-/-) patient and ATP13A2 knockdown cells are sensitive to zinc, whereas ATP13A2 over-expression in primary neurons confers zinc resistance. Reduced ATP13A2 expression significantly decreased vesicular zinc levels, indicating ATP13A2 facilitates transport of zinc into membrane-bound compartments or vesicles. Endogenous ATP13A2 localized to multi-vesicular bodies (MVBs), a late endosomal compartment located at the convergence point of the endosomal and autophagic pathways. Dysfunction in MVBs can cause a range of detrimental effects including lysosomal dysfunction and impaired delivery of endocytosed proteins/autophagy cargo to the lysosome, both of which have been observed in cells with reduced ATP13A2 function. MVBs also serve as the source of intra-luminal nanovesicles released extracellularly as exosomes that can contain a range of cargoes including α-Synuclein. Elevated ATP13A2 expression reduced intracellular α-Synuclein levels and increased α-Synuclein externalization in exosomes >3-fold whereas ATP13A2 knockdown decreased α-Synuclein externalization. An increased export of exosome-associated α-Synuclein may explain why surviving neurons of the substantia nigra pars compacta in sporadic PD patients were observed to over-express ATP13A2. We propose ATP13A2's modulation of zinc levels in MVBs can regulate the biogenesis of exosomes capable of containing α-Synuclein. Our data indicate that ATP13A2 is the first PD-associated gene involved in exosome biogenesis and indicates a potential neuroprotective role of exosomes in PD.
202 citations
TL;DR: The data provide insights into the molecular mechanisms of zinc dyshomeostasis in PD and its contribution to mitochondrial dysfunction with ATP13A2 as a molecular link between the two distinctive aetiological factors of PD.
Abstract: Human ATP13A2 (PARK9), a lysosomal type 5 P-type ATPase, has been associated with autosomal recessive early-onset Parkinson's disease (PD). ATP13A2 encodes a protein that is highly expressed in neurons and is predicted to function as a cation pump, although the substrate specificity remains unclear. Accumulation of zinc and mitochondrial dysfunction are established aetiological factors that contribute to PD; however, their underlying molecular mechanisms are largely unknown. Using patient-derived human olfactory neurosphere cultures, which harbour loss-of-function mutations in both alleles of ATP13A2, we identified a low intracellular free zinc ion concentration ([Zn(2+)]i), altered expression of zinc transporters and impaired sequestration of Zn(2+) into autophagy-lysosomal pathway-associated vesicles, indicating that zinc dyshomeostasis occurs in the setting of ATP13A2 deficiency. Pharmacological treatments that increased [Zn(2+)]i also induced the production of reactive oxygen species and aggravation of mitochondrial abnormalities that gave rise to mitochondrial depolarization, fragmentation and cell death due to ATP depletion. The toxic effect of Zn(2+) was blocked by ATP13A2 overexpression, Zn(2+) chelation, antioxidant treatment and promotion of mitochondrial fusion. Taken together, these results indicate that human ATP13A2 deficiency results in zinc dyshomeostasis and mitochondrial dysfunction. Our data provide insights into the molecular mechanisms of zinc dyshomeostasis in PD and its contribution to mitochondrial dysfunction with ATP13A2 as a molecular link between the two distinctive aetiological factors of PD.
128 citations
TL;DR: Clinical clues to a specific monogenic form of PD may be observed in some cases, but these manifestations are not universally present and patients with mutations in LRRK2 or multiplications in SNCA can be clinically indistinguishable from idiopathic PD.
Abstract: Parkinson's disease (PD) is a progressive neurological movement disorder characterised pathologically by degeneration of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies. Cardinal clinical features of PD are bradykinesia, rigidity, resting tremor, postural instability and responsiveness to levodopa. Identification of patients with causative variations in the PD-related genes (eg, SNCA , LRRK2 , Parkin , PINK1 , DJ-1 and ATP13A2 ) has been challenging given that only some patients have distinctive clinical phenotypes or a suggestive family history. Although clinical clues to a specific monogenic form of PD may be observed in some cases, for instance, behavioural problems and postural hypotension in patients with missense mutations in SNCA , early-onset dystonia in patients with mutations in Parkin and vertical gaze palsy, spasticity and facial-faucal mini-myoclonus in patients with mutations in ATP13A2 ,1 ,2 these manifestations are not universally present. Moreover, patients with mutations in LRRK2 or multiplications in SNCA can be clinically indistinguishable from idiopathic PD. Additionally, …