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

Abstract

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.

α-Synuclein and biological membranes: the danger of loving too much

“…There is a debate about the role of αS in mitochondrial morphology and dynamics, 101 with studies indicating that αS induces mitochondrial fragmentation 92,102,103 particularly when in the form of the PD variant A53T. 104 The underlying mechanisms of αS induced mitochondrial fragmentation are still unknown, with studies pointing to a direct involvement of the αS-membrane interaction.…”

Untitled

“…The rotenone-induced animal model reproduces the behavioural and pathological features of typical human PD 7 . This model replicates many aspects of PD, such as iron accumulation in the substantia nigra, systemic mitochondrial dysfunction, oxidative damage, microglial activation, selective nigrostriatal dopaminergic degeneration, L-doparesponsive motor deficits, impaired ubiquitinproteasome function, acidification and mitochondrial translocation of PARK7 (DJ-1) and gastrointestinal dysfunction associated with Alphasynuclein (α-Syn) aggregation and accumulation 8,9,10 . Since PD is mostly sporadic in humans with rare mutations, a study by Xicoy suggested that animal models were preferable to cell models like SH-SY5Y as clinical evidence correlated biochemically also 11 .…”

Insights from Single-Cell RNA-seq: Identifying the Actin Gene Family as Novel Drivers in Parkinson’s Disease

“…Significantly, the ACTB and ACTG1 genes are found to be shared among 9 out of the top 10 upregulated KEGG pathways and 18 out of the top 20. Thorne et al have detailed the association between Miro, alpha-Synuclein, and Actin in their study ( 3), adding depth to our understanding of these findings. The majority of the top downregulated KEGG pathways show a direct connection to PD (click on the pathway to see the reference).…”

“…Additionally, genetic studies have identified variations in Actin family genes in PD patients, highlighting their potential role as genetic drivers of the disease. Dysregulation of Actin polymerization and depolymerization processes may contribute to the formation of Lewy bodies and the degeneration of dopaminergic neurons ( 3). Understanding the role of the Actin family of genes in PD opens avenues for developing targeted therapeutic interventions.…”