Mitochondrial dynamics in Parkinson's disease: a role for α-synuclein?

Abstract

The distinctive pathological hallmarks of Parkinson's disease are the progressive death of dopaminergic neurons and the intracellular accumulation of Lewy bodies enriched in α-synuclein protein. Several lines of evidence from the study of sporadic, familial and pharmacologically induced forms of human Parkinson's disease also suggest that mitochondrial dysfunction plays an important role in disease progression. Although many functions have been proposed for α-synuclein, emerging data from human and animal models of Parkinson's disease highlight a role for α-synuclein in the control of neuronal mitochondrial dynamics. Here, we review the α-synuclein structural, biophysical and biochemical properties that influence relevant mitochondrial dynamic processes such as fusion-fission, transport and clearance. Drawing on current evidence, we propose that α-synuclein contributes to the mitochondrial defects that are associated with the pathology of this common and progressive neurodegenerative disease.

GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice

“…However, the pattern of downregulated fusion genes and upregulated fission genes seen here is more consistent with other parkinsonian animal models (Celardo, Martins, & Gandhi, 2014;Henchcliffe & Beal, 2008). The fact that α-synuclein overexpression induces mitochondrial fragmentation in several models (Pozo Devoto & Falzone, 2017) is consistent with the enhancement of fission gene (DRP1) expression noted in the current study (p = .01). Anti-α-synuclein siRNA transfection of neurons cocultured with TG astrocytes restored Mfn2 and DRP1 (Figure 7b, black bars), and to a lesser extent Mfn1, mRNA expression.…”

Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

“…Defects in mitochondrial dynamics, including the inhibition of mitochondrial fission and fusion, are responsible for many human diseases (Alexiou et al, ; Kim, Lee, Oh, Kim, & Han, ; Lenaers et al, ; Pozo Devoto & Falzone, ; Stuppia et al, ). Besides mutations in DNM1L (Waterham et al, ), dysfunctions in mitochondrial fission have been also associated with mutations in genes codifying for adaptors of DRP1, such as MFF and MID49/MIEF2 (Bartsakoulia et al, ; Koch et al, ; Shamseldin et al, ).…”

Regulation of Exocytosis and Mitochondrial Relocalization by Alpha-Synuclein in a Mammalian Cell Model

“…46,47,67,[80][81][82][83] Co-localization of a-syn with mitochondria is particularly intriguing as a-syn has been reported to interfere with mitochondrial fission/fusion, transport, and autophagy in neuronal systems, and disruption of these functional dynamics is associated with PD. 48 Indeed, the helical state of vesicle-bound a-syn is reminiscent of long amphipathic helices in mitofusions that facilitate mitochondrial membrane fusion, 84 and a-syn's capacities for interacting with other proteins, broken-helix binding, and curvature sensing could also affect fission/fusion and thereby other activities.…”

“…We also observed increased co-localization of Wt a-syn with the mitochondrial marker Mito-chameleon (Mt-cam) at higher expression levels ( Figures 6F, S7), as has been previously reported for HEK cells with a high degree of a-syn over-expression 47 and with neurons under some conditions. 48 A-syn co-localization with mitochondria increases after mitochondrial stress and involves helices 1 and 2. We quantified the association of transfected a-syn constructs with matrix-labeled mitochondria using both simple line scans ( Figure 6A-E) and more Figure 6.…”