Alpha-Synuclein and the Endolysosomal System in Parkinson’s Disease: Guilty by Association

Teixeira, Maxime; Sheta, Razan; Idi, Walid; Oueslati, Abid

doi:10.3390/biom11091333

Cited by 31 publications

(24 citation statements)

References 132 publications

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“…The anti-human α-Syn antibody [69] (hSyn, green) shows that the NII does not coincide with the distribution of the residual 1B fibrils (green) that are absent in the untreated control (Ctrl. column) and that are scattered on the whole neuronal surface and in some poorly delineated perikarial regions (empty arrowheads, probably the late endolysosomal compartment [70]). This shows that the NIIs do not correspond to an accumulation of the input fibrils.…”

Section: Niis Are Amyloid Assemblies Of Endogenous α-Synmentioning

confidence: 99%

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

et al. 2022

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The distinct neuropathological features of the different α-Synucleinopathies, as well as the diversity of the α-Synuclein (α-Syn) intracellular inclusion bodies observed in post mortem brain sections, are thought to reflect the strain diversity characterizing invasive α-Syn amyloids. However, this “one strain, one disease” view is still hypothetical, and to date, a possible disease-specific contribution of non-amyloid factors has not been ruled out. In Multiple System Atrophy (MSA), the buildup of α-Syn inclusions in oligodendrocytes seems to result from the terminal storage of α-Syn amyloid aggregates first pre-assembled in neurons. This assembly occurs at the level of neuronal cytoplasmic inclusions, and even earlier, within neuronal intranuclear inclusions (NIIs). Intriguingly, α-Syn NIIs are never observed in α-Synucleinopathies other than MSA, suggesting that these inclusions originate (i) from the unique molecular properties of the α-Syn fibril strains encountered in this disease, or alternatively, (ii) from other factors specifically dysregulated in MSA and driving the intranuclear fibrillization of α-Syn. We report the isolation and structural characterization of a synthetic human α-Syn fibril strain uniquely capable of seeding α-Syn fibrillization inside the nuclear compartment. In primary mouse cortical neurons, this strain provokes the buildup of NIIs with a remarkable morphology reminiscent of cat’s eye marbles (see video abstract). These α-Syn inclusions form giant patterns made of one, two, or three lentiform beams that span the whole intranuclear volume, pushing apart the chromatin. The input fibrils are no longer detectable inside the NIIs, where they become dominated by the aggregation of endogenous α-Syn. In addition to its phosphorylation at S129, α-Syn forming the NIIs acquires an epitope antibody reactivity profile that indicates its organization into fibrils, and is associated with the classical markers of α-Syn pathology p62 and ubiquitin. NIIs are also observed in vivo after intracerebral injection of the fibril strain in mice. Our data thus show that the ability to seed NIIs is a strain property that is integrally encoded in the fibril supramolecular architecture. Upstream alterations of cellular mechanisms are not required. In contrast to the lentiform TDP-43 NIIs, which are observed in certain frontotemporal dementias and which are conditional upon GRN or VCP mutations, our data support the hypothesis that the presence of α-Syn NIIs in MSA is instead purely amyloid-strain-dependent.

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Section: Niis Are Amyloid Assemblies Of Endogenous α-Synmentioning

confidence: 99%

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

et al. 2022

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“…This includes disruption to neurotransmitter release, intracellular trafficking and protein degradation amongst other processes, having a global impact on the cell that results in degeneration (Cooper et al, 2006;Sousa et al, 2009;Nemani et al, 2010). Of note, alphasynuclein oligomers have been shown to exert toxicity at mitochondria and throughout the endolysosomal system (Melo et al, 2018;Teixeira et al, 2021). Alpha-synuclein aggregates preferentially bind to mitochondria, not only reducing ATP production but also inducing fragmentation with subsequent impacts on mitophagy (Liu et al, 2009;Choubey et al, 2011;Wang et al, 2019).…”

Section: Alpha-synucleinmentioning

confidence: 99%

“…Alpha-synuclein's capacity to influence both mitochondrial and endolysosomal function pathologically suggests a significant impact for alpha-synuclein oligomers on mito-QC (Melo et al, 2018;Teixeira et al, 2021). Whether this could represent a key mechanism behind alpha-synuclein-induced cellular degeneration is an important question to be addressed.…”

Section: Alpha-synucleinmentioning

confidence: 99%

The relationship of alpha-synuclein to mitochondrial dynamics and quality control

Thorne

Tumbarello

2022

Front. Mol. Neurosci.

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Maintenance of mitochondrial health is essential for neuronal survival and relies upon dynamic changes in the mitochondrial network and effective mitochondrial quality control mechanisms including the mitochondrial-derived vesicle pathway and mitophagy. Mitochondrial dysfunction has been implicated in driving the pathology of several neurodegenerative diseases, including Parkinson’s disease (PD) where dopaminergic neurons in the substantia nigra are selectively degenerated. In addition, many genes with PD-associated mutations have defined functions in organelle quality control, indicating that dysregulation in mitochondrial quality control may represent a key element of pathology. The most well-characterized aspect of PD pathology relates to alpha-synuclein; an aggregation-prone protein that forms intracellular Lewy-body inclusions. Details of how alpha-synuclein exerts its toxicity in PD is not completely known, however, dysfunctional mitochondria have been observed in both PD patients and models of alpha-synuclein pathology. Accordingly, an association between alpha-synuclein and mitochondrial function has been established. This relates to alpha-synuclein’s role in mitochondrial transport, dynamics, and quality control. Despite these relationships, there is limited research defining the direct mechanisms linking alpha-synuclein to mitochondrial dynamics and quality control. In this review, we will discuss the current literature addressing this association and provide insight into the proposed mechanisms promoting these functional relationships. We will also consider some of the alternative mechanisms linking alpha-synuclein with mitochondrial dynamics and speculate what the relationship between alpha-synuclein and mitochondria might mean both physiologically and in relation to PD.

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“…The researchers hypothesize that fibroblast-derived from patients harboring GBA1 mutations promote changes in the lipid composition of recipient cells, which may account for the increased phospho-α-syn, posttraductional modification that increases the formation of insolubleα-syn forms ( Canerina-Amaro et al, 2019 ). Besides releasing exosomes, MVBs can be eliminated through the ALP by a direct fusion with lysosomes or autophagosomes ( Fader et al, 2008 ; Vanlandingham and Ceresa, 2009 ; Szatmari et al, 2014 ; Teixeira et al, 2021 ). α-syn itself can disturb the ALP activity, promoting potential positive feedback to its secretion.…”

Section: Impact Of Autophagy-lysosomal Pathway In Parkinson’s Disease...mentioning

confidence: 99%

Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease

Sepúlveda

Cisternas-Olmedo

Arcos

et al. 2022

Front. Mol. Neurosci.

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Parkinson’s disease (PD) is caused by the degeneration of dopaminergic neurons due to an accumulation of intraneuronal abnormal alpha-synuclein (α-syn) protein aggregates. It has been reported that the levels of exosomal α-syn of neuronal origin in plasma correlate significantly with motor dysfunction, highlighting the exosomes containing α-syn as a potential biomarker of PD. In addition, it has been found that the selective autophagy-lysosomal pathway (ALP) contributes to the secretion of misfolded proteins involved in neurodegenerative diseases. In this review, we describe the evidence that supports the relationship between the ALP and α-syn exosomal secretion on the PD progression and its implications in the diagnosis and progression of this pathology.

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Alpha-Synuclein and the Endolysosomal System in Parkinson’s Disease: Guilty by Association

Cited by 31 publications

References 132 publications

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

The relationship of alpha-synuclein to mitochondrial dynamics and quality control

Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease

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