Autophagy and <scp>A</scp>lpha‐<scp>S</scp>ynuclein: <scp>R</scp>elevance to <scp>P</scp>arkinson's <scp>D</scp>isease and <scp>R</scp>elated <scp>S</scp>ynucleopathies

Xilouri, Maria; Brekk, Oeystein Roed; Stefanis, Leonidas

doi:10.1002/mds.26477

Cited by 235 publications

(190 citation statements)

References 149 publications

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“…Numerous studies have indicated that autophagy is involved in the pathological changes observed in PD (25–27). However, the explicit role of autophagy in iron-induced pathology is still uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…In the last decade, growing evidence has indicated an intimate relationship between autophagy and PD, showing that autophagy dysregulation may play a critical role in the development of PD. Aggregates of α-synuclein are mainly degraded via the autophagy pathway (25–27), including macroautophagy and CMA pathways (24). The autophagy signaling pathway has been reported to be disrupted in PD (28).…”

Section: Introductionmentioning

confidence: 99%

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Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

et al. 2017

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Growing evidence has indicated that iron deposition in the substantia nigra plays an important role in Parkinson’s disease (PD). However, the underlying mechanism is still elusive. Using primary dopaminergic neurons and SH-SY5Y cells cultured in vitro, we observed that iron loading increased α-synuclein and reactive oxygen species (ROS) levels in these cells but did not affect the intracellular α-synuclein mRNA levels. Furthermore, iron loading significantly downregulated Beclin-1 levels and decreased the ratio of microtubule-associated protein 1 light chain 3 isoforms (LC3 II/LC3 I). However, a significant change in the levels of autophagy-related gene 5 (Atg5) was not observed in either neurons or SH-SY5Y cells after iron treatment. After treatment with rapamycin, the iron loading-induced increase in the α-synuclein level was significantly reversed and ROS generation was alleviated in both cultured neurons and SH-SY5Y cells. These results indicate that the inhibition of autophagy is critical for the pathological alterations in α-synuclein induced by iron loading. Moreover, treatment with vitamin E did not affect the increase in the α-synuclein levels but significantly eliminated the iron-induced ROS production. Together, our study shows that autophagy dysfunction contributes to iron-induced α-synuclein pathology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

et al. 2017

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“…Defects in autophagy and lysosomal function have both been observed in PD (Lynch-Day et al, 2012; Nixon, 2013; Xilouri et al, 2016). One of the strongest links between lysosomal function and PD is found with the enzyme β-glucocerebrosidase (GBA) (Table 1, Fig.…”

Section: Intracellular Ca2+ Stores and Their Deregulation In Pdmentioning

confidence: 99%

The role of Ca2+ signaling in Parkinson's disease

Zaichick

McGrath

Caraveo

2017

Disease Models &Amp; Mechanisms

147

101

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Across all kingdoms in the tree of life, calcium (Ca2+) is an essential element used by cells to respond and adapt to constantly changing environments. In multicellular organisms, it plays fundamental roles during fertilization, development and adulthood. The inability of cells to regulate Ca2+ can lead to pathological conditions that ultimately culminate in cell death. One such pathological condition is manifested in Parkinson's disease, the second most common neurological disorder in humans, which is characterized by the aggregation of the protein, α-synuclein. This Review discusses current evidence that implicates Ca2+ in the pathogenesis of Parkinson's disease. Understanding the mechanisms by which Ca2+ signaling contributes to the progression of this disease will be crucial for the development of effective therapies to combat this devastating neurological condition.

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“…An additional interesting hub gene in this module is Bloc1s1 . Bloc1s1 is a component of the BLOC-1 complex, which is involved in the biogenesis of lysosome-related organelle, suggesting a potential influence on lysosomal degradation of aggregates or dysfunctional organelles, both of which have been strongly implicated in synucleinopathies [17, 34, 50, 106]. In addition, the BLOC-1 complex is also involved in the negative regulation of aerobic respiration through mitochondrial protein lysine-acetylation [88, 89].…”

Section: Resultsmentioning

confidence: 99%

Integrated analysis of genetic, behavioral, and biochemical data implicates neural stem cell-induced changes in immunity, neurotransmission and mitochondrial function in Dementia with Lewy Body mice

Lakatos

Goldberg

Blurton‐Jones

2017

acta neuropathol commun

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We previously demonstrated that transplantation of murine neural stem cells (NSCs) can improve motor and cognitive function in a transgenic model of Dementia with Lewy Bodies (DLB). These benefits occurred without changes in human α-synuclein pathology and were mediated in part by stem cell-induced elevation of brain–derived neurotrophic factor (BDNF). However, instrastriatal NSC transplantation likely alters the brain microenvironment via multiple mechanisms that may synergize to promote cognitive and motor recovery. The underlying neurobiology that mediates such restoration no doubt involves numerous genes acting in concert to modulate signaling within and between host brain cells and transplanted NSCs. In order to identify functionally connected gene networks and additional mechanisms that may contribute to stem cell-induced benefits, we performed weighted gene co-expression network analysis (WGCNA) on striatal tissue isolated from NSC- and vehicle-injected wild-type and DLB mice. Combining continuous behavioral and biochemical data with genome wide expression via network analysis proved to be a powerful approach; revealing significant alterations in immune response, neurotransmission, and mitochondria function. Taken together, these data shed further light on the gene network and biological processes that underlie the therapeutic effects of NSC transplantation on α-synuclein induced cognitive and motor impairments, thereby highlighting additional therapeutic targets for synucleinopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0421-0) contains supplementary material, which is available to authorized users.

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Autophagy and Alpha‐Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies

Cited by 235 publications

References 149 publications

Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

The role of Ca2+ signaling in Parkinson's disease

Integrated analysis of genetic, behavioral, and biochemical data implicates neural stem cell-induced changes in immunity, neurotransmission and mitochondrial function in Dementia with Lewy Body mice

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