Activation of  -Glucocerebrosidase Reduces Pathological  -Synuclein and Restores Lysosomal Function in Parkinson's Patient Midbrain Neurons

Abstract

Parkinson's disease (PD) is characterized by the accumulation of ␣-synuclein (␣-syn) within Lewy body inclusions in the nervous system. There are currently no disease-modifying therapies capable of reducing ␣-syn inclusions in PD. Recent data has indicated that loss-offunction mutations in the GBA1 gene that encodes lysosomal ␤-glucocerebrosidase (GCase) represent an important risk factor for PD, and can lead to ␣-syn accumulation. Here we use a small-molecule modulator of GCase to determine whether GCase activation within lysosomes can reduce ␣-syn levels and ameliorate downstream toxicity. Using induced pluripotent stem cell (iPSC)-derived human midbrain dopamine (DA) neurons from synucleinopathy patients with different PD-linked mutations, we find that a non-inhibitory small molecule modulator of GCase specifically enhanced activity within lysosomal compartments. This resulted in reduction of GCase substrates and clearance of pathological ␣-syn, regardless of the disease causing mutations. Importantly, the reduction of ␣-syn was sufficient to reverse downstream cellular pathologies induced by ␣-syn, including perturbations in hydrolase maturation and lysosomal dysfunction. These results indicate that enhancement of a single lysosomal hydrolase, GCase, can effectively reduce ␣-syn and provide therapeutic benefit in human midbrain neurons. This suggests that GCase activators may prove beneficial as treatments for PD and related synucleinopathies.

Role of microRNAs in the Regulation of α-Synuclein Expression: A Systematic Review

“…Interestingly, miR-7 played a role in insulin secretion by repressing the expression of α-synuclein which in turn modulated the granule fusion with the plasma membrane. These results are in line with the previous observation that α-synuclein, whose exact function still remains unknown, plays a role in neurotransmitter release via regulating the pool of vesicles available in the synaptic bouton and its fusion with the plasma membrane (Murphy et al, 2000; Cabin et al, 2002; Fernández-Chacón et al, 2004; Chandra et al, 2005; Larsen et al, 2006; Mazzulli et al, 2016). …”

“…Supporting evidence includes: (i) duplications and triplication of the α-synuclein gene cause dominantly inherited PD, with a dose-correlation of α-synuclein load to the PD phenotype (Singleton et al, 2003; Ibáñez et al, 2004, 2009; Ahn et al, 2008; Ross et al, 2008); (ii) polymorphisms in α-synuclein promoters are associated with increased PD risk by enhancing α-synuclein expression (Chiba-Falek and Nussbaum, 2001; Touchman et al, 2001; Maraganore et al, 2006); (iii) increased α-synuclein mRNA levels are found in surviving dopaminergic (DA) neurons in the substantia nigra (SN) of idiopathic PD patients (Gründemann et al, 2008); (iv) induced pluripotent stem cells (iPS) from PD patients exhibited α-synuclein accumulation (Nguyen et al, 2011; Sánchez-Danés et al, 2012; Mazzulli et al, 2016); (v) α-synuclein is up-regulated in several in vivo PD models including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice and monkeys (Vila et al, 2000, 2001; Purisai et al, 2005); and (vi) overexpression of human wild-type and A53T mutant α-synuclein in rats and monkeys induced nigrostriatal degeneration (Kirik et al, 2002, 2003). In addition to PD, α-synuclein plays a key role in and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA; Tagliafierro and Chiba-Falek, 2016).…”

Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease

“…Dopaminergic neurons from idiopathic PD patients (iPD1, (11); iPD2, fig. S1, E and F) also manifested a similar phenotype, including decreased basal respiration and oxidized dopamine accumulation, but at later time points (d150, d180) (Fig.…”

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

“…In contrast, some reports indicate that the C-terminal acidic tail is indeed necessary but not sufficient for the chaperone function of α-Syn [28,29]. In normal physiological conditions, α-Syn exists in monomeric form and is recognized and cleared via the ubiquitin-proteasome system (UPS) and chaperone-mediated autophagy (CMA) pathways [39] (Figure 2). In the pathological state, misfolding or mutations of α-Syn (A30P/A53T) lead to the formation of pathologically modified species that bind with several cytoplasmic proteins and ultimately aggregate into LBs in the DA neuronal cells [40] ( Figure 2).…”