The protein α-synuclein, which is widely distributed in the nervous system, plays a central role in the development of Parkinson's disease, which is characterised by α-synuclein aggregates in so-called Lewy bodies in the brain. Rare missense mutations in the SNCA gene, which encodes α-synuclein, but also the more common duplications (duplications or triplications) of the SNCA gene, lead to autosomal-dominantly inherited Parkinson's disease. The pathogenic effects of increased SNCA gene expression suggest that an increase in α-synuclein levels is sufficient to cause Parkinson's symptoms.
Interestingly, genetic changes (polymorphisms) in regulatory elements of the SNCA gene have also been described as risk factors for sporadic Parkinson's disease, and high levels of α-synuclein proteins are common in dopaminergic neurons in older people, which may explain why age is a strong risk factor for PD.
α-Synuclein is a 140 amino acid long protein that is enriched in presynaptic axonal terminals. Under pathological conditions, α-synuclein can misfold and aggregate into oligomers, protofibrils and insoluble fibrils. Misfolded α-synuclein may also spread between neurons and promote further conformational changes of α-synuclein in a prion-like manner.
Although pathological α-synuclein can cause neurotoxicity by disrupting intracellular metabolism, there is evidence that the induction of damage in mitochondria is one of the key pathological mechanisms. Pathologically modified α-synuclein binds to mitochondrial membranes, impairs electron transport in the respiratory chain and disrupts mitochondrial protein import.
Mitochondria that have undergone such changes are normally removed by mitophagy. This is a quality control pathway in which damaged mitochondria are selectively enclosed by autophagosomes and then broken down in lysosomes. Three proteins are directly relevant to Parkinson's disease: PINK1, Parkin and DJ-1, which are altered in autosomal recessive forms of Parkinson's.
Normally, the Parkin kinase PINK1 accumulates selectively on the outer mitochondrial membrane of damaged mitochondria and activates Parkin to ubiquitinate several proteins of the outer mitochondrial membrane. In neurons, the autophagy receptor optineurin is then recruited to mitochondrial ubiquitin chains in a DJ-1-dependent manner and links ubiquitin to LC3, which is present on autophagosomal membranes. This mechanism allows the inclusion of defective mitochondria by autophagosomes and is essential to keep post-mitotic neurons functionally active for many years.
In a study published this year in the Nature journal npj Parkinson's Disease, scientists led by Wim Vandenberghe in Leuven, Belgium, quantified mitophagy and non-mitochondrial autophagy in three models with increased α-synuclein expression: in the fruit fly Drosophila melanogaster, which expresses human α- synuclein in their flight muscles; then in human skin fibroblasts transfected with α-synuclein or β-synuclein; and in neurons derived from human induced pluripotent stem cells (iPSCs) that contained an extra copy of SNCA under the control of a doxycycline-inducible promoter.
In each model, elevated α-synuclein levels strongly suppressed mitophagy, while non-mitochondrial autophagy was maintained. In human neurons, doubling the wild-type α-synuclein was enough to induce this effect. The activation of PINK1 and Parkin as well as the mitochondrial translocation of DJ-1 after mitochondrial depolarisation was not affected by the α-synuclein overexpression.
Overexpression of the actin-splitting protein cofilin or treatment with CK666, an inhibitor of the actin-related protein 2/3 (Arp2/3) complex, rescued mitophagy in neurons with elevated α-synuclein , suggesting that excessive stabilisation of the actin network mediated the mitophagy defect, leading the authors to suspect that disruption of actin dynamics plays a key role in α-synuclein-dependent mitophagy disruption.
Reference:
Kinnart I, Manders L, Heyninck T, Imberechts D, Praschberger R, Schoovaerts N, Verfaillie C, Verstreken P, Vandenberghe W (2024) Elevated α-synuclein levels inhibit mitophagic flux. npj Parkinson's Disease 10:80
Image credit: iStock/Artur Plawgo
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