The Close Encounter Between Alpha-Synuclein and Mitochondria

Abstract

The presynaptic protein alpha-synuclein (α-syn) is unequivocally linked to the development of Parkinson’s disease (PD). Not only it is the major component of amyloid fibrils found in Lewy bodies but mutations and duplication/triplication in its gene are responsible for the onset of familial autosomal dominant forms of PD. Nevertheless, the precise mechanisms leading to neuronal degeneration are not fully understood. Several lines of evidence suggest that impaired autophagy clearance and mitochondrial dysfunctions such as bioenergetics and calcium handling defects and alteration in mitochondrial morphology might play a pivotal role in the etiology and progression of PD, and indicate the intriguing possibility that α-syn could be involved in the control of mitochondrial function both in physiological and pathological conditions. In favor of this, it has been shown that a fraction of cellular α-syn can selectively localize to mitochondrial sub-compartments upon specific stimuli, highlighting possible novel routes for α-syn action. A plethora of mitochondrial processes, including cytochrome c release, calcium homeostasis, control of mitochondrial membrane potential and ATP production, is directly influenced by α-syn. Eventually, α-syn localization within mitochondria may also account for its aggregation state, making the α-syn/mitochondria intimate relationship a potential key for the understanding of PD pathogenesis. Here, we will deeply survey the recent literature in the field by focusing our attention on the processes directly controlled by α-syn within mitochondrial sub-compartments and its potential partners providing possible hints for future therapeutic targets.

The interactome of stabilized α‐synuclein oligomers and neuronal proteins

“…V‐ATPase maintains a steady‐state pH, so binding of αSOs to V‐ATPase might disrupt lysosomal acidification and lead to abnormal Ca 2+ homeostasis . Binding of αSO to the outer mitochondrial membrane protein VDAC also affects Ca 2+ signalling within mitochondria . Given that there are multiple binding sites on each αSO, it is possible that one αSO could interfere with several different pathways simultaneously with even greater cellular impact.…”

“…These mechanisms include interactions with cellular components, such as membranes and synaptic proteins . αSOs have also been proposed to lead to abnormal Ca 2+ homeostasis through deleterious interactions with membrane proteins such as ras‐related protein 3A (Rab‐3A), the sodium–potassium pump Na + /K + ‐ATPase (NKA), the V‐type proton ATPase (V‐ATPase), the voltage‐dependent anion channel (VDAC) and calcium‐/calmodulin‐dependent protein kinase type II (CAMKII) . There is also evidence for αSO interference with proteins in synapses.…”

Systemic Activation of Nrf2 Pathway in Parkinson's Disease

“…Synucleinopathy and mitochondrial dysfunction are partners in crime that critically contribute to pathogenesis and progression of PD. In fact, mitochondrial impairment causes cellular redox imbalance and concurs to α‐syn misfolding/aggregation . Likewise, the different α‐syn species can selectively localize to mitochondrial compartments, impairing their functions .…”

“…In fact, mitochondrial impairment causes cellular redox imbalance and concurs to α‐syn misfolding/aggregation . Likewise, the different α‐syn species can selectively localize to mitochondrial compartments, impairing their functions . Moreover, they can also activate the Nrf2 pathway synergistically …”

“…3,29,30 Likewise, the different α-syn species can selectively localize to mitochondrial compartments, impairing their functions. 29,30 Moreover, they can also activate the Nrf2 pathway synergistically. 12,[31][32][33] We found that α-syn oligomers, whose increase in cerebrospinal fluid or other blood fractions of PD patients is now considered a marker of synucleinopathy, 17,[34][35][36][37][38] were increased even in the peripheral leukocytes of PD patients.…”