α-Synuclein–induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models

Abstract

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

A novel floor plate boundary defined by adjacentEn1andDbx1microdomains distinguishes midbrain dopamine and hypothalamic neurons

“…Thus, it is possible that in our En1OE model, modest expression levels achieved in the early embryo were not sufficient for complete reprogramming of the Dbx1 + mdFP to DA neurons. Recent advances in the generation of DA neurons from stem cells have shown promising results towards potential cell replacement therapies and modeling studies for Parkinson's disease (Cooper et al, 2012;Grealish et al, 2014;Kirkeby et al, 2012;Kriks et al, 2011;Mazzulli et al, 2016;Xi et al, 2012). Key protocols designed for the conversion of induced pluripotent stem cells (iPSCs) into DA neurons were based on previous developmental studies showing DA neurons arise from FP progenitors, and use FOXA2 and LMX1A to optimize DA neuron derivation protocols (Kirkeby et al, 2012;Kriks et al, 2011;Xi et al, 2012).…”

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

“…2C). In order to determine if other forms of genetic PD might show similar alterations, we generated iPSC-derived neurons from PD patients with homozygous mutations in the parkin, PINK1 , and LRRK2 (15, 16) genes and neurons carrying triplication of wildtype (WT) α-synuclein (17). We observed a similar increase in oxidized dopamine across all genotypes (fig.…”

Bibenzyl compound 20c protects against endoplasmic reticulum stress in tunicamycin-treated PC12 cells in vitro

“…The aggregation of α-syn leads to lysosomal dysfunction [21] , membrane disruption [22] , and dopaminergic neuron disorders [20] . Numerous studies have proposed that the aggregation of α-syn or the increased Ser129 phosphorylation of α-syn are co-localized with UPR activation [23,24] .…”

“…Additionally, the two forms of α-syn accumulated in the ER and mitochon- dria after treatment with tunicamycin, which suggests that ER stress was an active participant in the process of α-syn accumulation. Moreover, our studies provide evidence that 20c exerts protective effects on tunicamycin-treated PC12 cells, reduces the expression of α-syn and inhibits the activation of the UPR, which suggest that 20c is a neuroprotective compound worthy of future study.The aggregation of α-syn leads to lysosomal dysfunction [21] , membrane disruption [22] , and dopaminergic neuron disorders [20] . Numerous studies have proposed that the aggregation of α-syn or the increased Ser129 phosphorylation of α-syn are co-localized with UPR activation [23,24] .…”