The protein α-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of α-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by α- than β- or γ-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. α-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease.
"ion , which could arise from an increase in mitochondrial energy production from fatty acid or amino acid oxidation upon glucose deprivation . Consistent with the proposal that networked mitochondria generate less oxidative stress , mitochondrial fission has been shown to contribute to excessive ROS production in other models ( Yu et al . , 2006 ; Nakamura et al . , 2011 ) . How mitochondrial connectivity affects ROS accumulation is a crucial issue that awaits further investigation . However , we noticed that HDAC6 - , MFN1 - and OPA1 - KO MEFs all showed some degrees of elevated mitochondrial membrane potential ( supplementary material Fig . S3E ) , which has been proposed to increase the electron back"
[Show abstract][Hide abstract] ABSTRACT: Fasting and glucose shortage activate a metabolic switch that shifts more energy production to mitochondria. This metabolic adaptation ensures energy supply, but also elevates the risk of mitochondrial oxidative damage. Here we present evidence that metabolically challenged mitochondria undergo active fusion to suppress oxidative stress. In response to glucose starvation, mitofusin 1 (MFN1) becomes associated with the protein deacetylase HDAC6. This interaction leads to MFN1 deacetylation and activation, promoting mitochondrial fusion. Deficiency in HDAC6 or MFN1 prevents mitochondrial fusion induced by glucose deprivation. Unexpectedly, failure to undergo fusion does not acutely affect mitochondrial adaptive energy production; instead, it causes excessive mitochondrial reactive oxygen species and oxidative damage, a defect suppressed by an acetylation-resistant MFN1 mutant. In mice subjected to fasting, skeletal muscle mitochondria undergo dramatic fusion. Remarkably, fasting-induced mitochondrial fusion is abrogated in HDAC6 knockout mice, resulting in extensive mitochondrial degeneration. These findings show that adaptive mitochondrial fusion protects metabolically challenged mitochondria.
Journal of Cell Science 09/2014; DOI:10.1242/jcs.157321 · 5.43 Impact Factor
"Of importance, α-syn seems to induce cell toxicity through its different pathological α-syn species, which include post-translationally modified, mutant, oligomeric and aggregated forms. These can (i) disrupt its typical function in neurotransmission release (Abeliovich et al., 2000; Jenco et al., 1998); (ii) impair mitochondrial dynamics, structure and function (Martin et al., 2006; Nakamura et al., 2011; Stefanovic et al., 2014); and (iii) disrupt ER-Golgi vesicle trafficking (Cooper et al., 2006; Gitler et al., 2008) and mitochondria-associated ER membrane (Mercado et al., 2013; Guardia-Laguarta et al., 2014), which results in ER stress. Further supporting the α-syn species toxicity, CMA inhibition by either PD-linked α-syn mutants or dopamine-modified wild-type α-syn results in an accumulation of α-syn, but also of undegraded CMA-substrates, involved for instance in the regulation of neuronal survival through the degradation of the neuronal survival factor myocyte enhancer factor 2D (MEF2D; Yang et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Neurodegenerative diseases are (i) characterized by a selective neuronal vulnerability to degeneration in specific brain regions; and (ii) likely to be caused by disease-specific protein misfolding. Parkinson's disease (PD) is characterized by the presence of intraneuronal proteinacious cytoplasmic inclusions, called Lewy Bodies (LB). α-Synuclein, an aggregation prone protein, has been identified as a major protein component of LB and the causative for autosomal dominant PD. Lysosomes are responsible for the clearance of long-lived proteins, such as α-synuclein, and for the removal of old or damaged organelles, such as mitochondria. Interestingly, PD-linked α-synuclein mutants and dopamine-modified wild-type α-synuclein block its own degradation, which result in insufficient clearance, leading to its aggregation and cell toxicity. Moreover, both lysosomes and lysosomal proteases have been found to be involved in the activation of certain cell death pathways. Interestingly, lysosomal alterations are observed in the brains of patients suffering from sporadic PD and also in toxic and genetic rodent models of PD-related neurodegeneration. All these events have unraveled a causal link between lysosomal impairment, α-synuclein accumulation, and neurotoxicity. In this review, we emphasize the pathophysiological mechanisms connecting α-synuclein and lysosomal dysfunction in neuronal cell death.
Frontiers in Neuroanatomy 08/2014; 8(83). DOI:10.3389/fnana.2014.00083 · 3.54 Impact Factor
"These mitochondria often presented with a swollen pathological morphology, although this was not always the case. Indeed, mitochondrial dysfunction has been identified as one of the hallmarks of α-synuclein toxicity and is thought to play a major role in neuronal degeneration , . "
[Show abstract][Hide abstract] ABSTRACT: Synucleinopathies, characterized by intracellular aggregation of α-synuclein protein, share a number of features in pathology and disease progression. However, the vulnerable cell population differs significantly between the disorders, despite being caused by the same protein. While the vulnerability of dopamine cells in the substantia nigra to α-synuclein over-expression, and its link to Parkinson's disease, is well studied, animal models recapitulating the cortical degeneration in dementia with Lewy-bodies (DLB) are much less mature. The aim of this study was to develop a first rat model of widespread progressive synucleinopathy throughout the forebrain using adeno-associated viral (AAV) vector mediated gene delivery. Through bilateral injection of an AAV6 vector expressing human wild-type α-synuclein into the forebrain of neonatal rats, we were able to achieve widespread, robust α-synuclein expression with preferential expression in the frontal cortex. These animals displayed a progressive emergence of hyper-locomotion and dysregulated response to the dopaminergic agonist apomorphine. The animals receiving the α-synuclein vector displayed significant α-synuclein pathology including intra-cellular inclusion bodies, axonal pathology and elevated levels of phosphorylated α-synuclein, accompanied by significant loss of cortical neurons and a progressive reduction in both cortical and striatal ChAT positive interneurons. Furthermore, we found evidence of α-synuclein sequestered by IBA-1 positive microglia, which was coupled with a distinct change in morphology. In areas of most prominent pathology, the total α-synuclein levels were increased to, on average, two-fold, which is similar to the levels observed in patients with SNCA gene triplication, associated with cortical Lewy body pathology. This study provides a novel rat model of progressive cortical synucleinopathy, showing for the first time that cholinergic interneurons are vulnerable to α-synuclein over-expression. This animal model provides a powerful new tool for studies of neuronal degeneration in conditions of widespread cortical α-synuclein pathology, such as DLB, as well an attractive model for the exploration of novel biomarkers.
PLoS ONE 07/2014; 9(7):e100869. DOI:10.1371/journal.pone.0100869 · 3.23 Impact Factor
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