Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production

Tapias, Vı́ctor; Hu, Xiaoping; Luk, Kelvin C.; Sanders, Laurie H.; Lee, Virginia M.; Greenamyre, J. Timothy

doi:10.1007/s00018-017-2541-x

Cited by 104 publications

(121 citation statements)

References 65 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…Other studies also did not report DA cell loss at 7 days post-PFFs, and modest cell loss 18 was observed after longer periods (i.e. 14 days post PFFs) and/or additional neurotoxic insult to the 19 cells (Tapias et al, 2017;Volpicelli-Daley et al, 2014). Moreover, the lack of cell death at the early time 20 points after induction of the pathological α-syn aggregation is consistent with reports showing that 21 while the rodents injected with PFFs develop robust α-syn aggregation, such loss of DA neurons was 22 observed only several months after PFF treatment.…”

Section: [Main Text]mentioning

confidence: 97%

GDNF/RET signaling pathway activation eliminates Lewy Body pathology in midbrain dopamine neurons

Chmielarz

Konovalova

et al. 2019

Preprint

View full text Add to dashboard Cite

Neurodegenerative diseases are associated with proteostasis disturbances and accumulation of fibrillar proteins into insoluble aggregates. Progressive age-related degeneration of dopamine neurons is a primary cause of motor dysfunctions in Parkinson’s disease (PD) and substantial evidence supports critical involvement of α-synuclein (α-syn) in the etiology of PD. α-syn is a cytosolic protein present in high concentrations in pre-synaptic neuronal terminals and a primary constituent of intracellular protein aggregates known as Lewy Neurites or Lewy Bodies. Progression of Lewy pathology is a characteristic feature in the PD brains caused by the prion-like self-templating properties of misfolded α-syn. Modelling Lewy pathology progression with application of exogenously prepared α-syn preformed fibrils, we discovered that glial cell line-derived neurotrophic factor (GDNF) prevented formation of α-syn aggregates in dopamine neurons in culture and in vivo after viral vector expression of GDNF. These effects were abolished by CRISPR/Cas9-mediated deletion of receptor tyrosine kinase Ret, the major GDNF signaling pathway. Similar to GDNF, expression of mutated constitutively active RET (RET_MEN2B) was able to protect dopamine neurons. GDNF protection against α-syn pathology progression was abolished by Src and attenuated by Akt pathway inhibitors. For the first time, we have shown the neurotrophic factor-mediated protection against the misfolded α-syn propagation in dopamine neurons, uncovered underlying receptor and intracellular signaling pathways. These results for the first time demonstrate that activation of GDNF/RET signaling can be an effective therapeutic approach to prevent Lewy pathology spread at early stages of PD.

show abstract

Section: [Main Text]mentioning

confidence: 97%

GDNF/RET signaling pathway activation eliminates Lewy Body pathology in midbrain dopamine neurons

Chmielarz

Konovalova

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Abnormally high levels of mitochondrial Ca 2+ triggers apoptosis. Therefore, α-syn may induce apoptotic cell degradation in a mitochondrial-linked pathway and caspase activation (Smith et al 2005; Parihar et al 2008), making mitochondria cellular targets of α-syn accumulation and neurotoxicity (Di Maio et al 2016; Wong and Krainc 2017; Tapias et al 2017). A mitochondrial-independent pathway has also been suggested, whereby α-syn oligomers are thought to interfere with the normal functions of cell membranes and form pore-like structures in lipid bilayers that leads to abnormal Ca 2+ influx and subsequent neuronal cell damage (Tsigelny et al 2012).…”

Section: Does the Aggregation And Propagation Of α-Syn Correlate Withmentioning

confidence: 99%

The concept of alpha-synuclein as a prion-like protein: ten years after

2018

View full text Add to dashboard Cite

Parkinson's disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson's disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson's disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha-synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha-synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion-like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson's disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson's disease.

show abstract

“…Decreased respiration has already been shown in previous studies in the neuronal seeding model. However, respiration was assessed only between 8/9 and 14 days after PFFs treatment using mouse cortical neurons 94 or rat midbrain neurons95 , respectively. Importantly, in these previous studies high PFF concentrations (140nM or 350nM) were used, which in our hands induce cell death events faster.…”

mentioning

confidence: 99%

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

Mahul‐Mellier

Burtscher

Maharjan

et al. 2019

Preprint

View full text Add to dashboard Cite

Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LB). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD and synucleinopathies, the processes that govern α-syn fibrillization and LB formation in the brain remain poorly understood. In this work, we sought to reverse engineer LBs and dissect the spatiotemporal events involved in their biogenesis at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we took advantage of a seeding-based model of α-syn fibril formation in primary neurons and further developed this model to generate the first neuronal model that reproduces the key events leading to LB formation; including seeding, fibrillization, and the formation of LB-like inclusions that recapitulate many of the biochemical, structural, and organizational features of LBs found in post-mortem human PD brain tissues. Next, we applied an integrative approach combining confocal and correlative light-electron microscopy (CLEM) imaging methods with biochemical profiling of α-syn species and temporal proteomic and transcriptomic analyses to dissect the molecular events associated with LB formation and maturation and to elucidate their contributions to neuronal dysfunctions and neurodegeneration in PD and synucleinopathies. The results from these studies demonstrate that LB formation involves a complex interplay between α-syn fibrillization, post-translational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria and the autophagosome and endolysosome. Furthermore, we demonstrate that the process of LB formation and maturation, rather than simply fibril formation, is the major driver of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, as well as synaptic dysfunctions. Having a neuronal model that allows for unlinking of the key processes involved in LB formation is crucial for elucidating the molecular and cellular determinants of each process and their contributions to neuronal dysfunction and degeneration in PD and synucleinopathies. Such a model is essential to efforts to identify and investigate the mode of action and toxicity of drug candidates targeting α-syn aggregation and LB formation.

show abstract

Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production

Cited by 104 publications

References 65 publications

GDNF/RET signaling pathway activation eliminates Lewy Body pathology in midbrain dopamine neurons

GDNF/RET signaling pathway activation eliminates Lewy Body pathology in midbrain dopamine neurons

The concept of alpha-synuclein as a prion-like protein: ten years after

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

Contact Info

Product

Resources

About