The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation

Abstract

α-synuclein (aSyn) is associated with both sporadic and familial forms of Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease. In particular, multiplications and point mutations in the gene encoding for aSyn cause familial forms of PD. Moreover, the accumulation of aSyn in Lewy Bodies and Lewy neurites in disorders such as PD, dementia with Lewy bodies, or multiple system atrophy, suggests aSyn misfolding and aggregation plays an important role in these disorders, collectively known as synucleinopathies. The exact function of aSyn remains unclear, but it is known to be associated with vesicles and membranes, and to have an impact on important cellular functions such as intracellular trafficking and protein degradation systems, leading to cellular pathologies that can be readily studied in cell-based models. Thus, understanding the molecular effects of aSyn point mutations may provide important insight into the molecular mechanisms underlying disease onset.We investigated the effect of the recently identified A53E aSyn mutation. Combining in vitro studies with studies in cell models, we found that this mutation reduces aSyn aggregation and increases proteasome activity, altering normal proteostasis.We observed that, in our experimental paradigms, the A53E mutation affects specific steps of the aggregation process of aSyn and different cellular processes, providing novel ideas about the molecular mechanisms involved in synucleinopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0402-8) contains supplementary material, which is available to authorized users.

Parkinsonism due to A53E α‐synuclein gene mutation: Clinical, genetic, epigenetic, and biochemical features

“…To investigate how A53E may lead to neurodegeneration, earlier in vitro studies examined its effects on α‐synuclein aggregation properties . They demonstrated that A53E α‐synuclein spends a protracted time in oligomeric forms with delayed β‐sheet‐containing fibril formation compared with WT α‐synuclein.…”

“…CD spectra of unphosphorylated A53E demonstrated a random coil conformation on day 7, which remained unchanged after 13 days of incubation. EM revealed only amorphous oligomers; no fibrils formed after prolonged incubation periods of 7 and 13 days, consistent with prior studies . With phosphorylation of A53E, CD spectra consistent with a more β‐sheet conformation was observed after 7 days of incubation, and transition to typical β‐sheet was complete on day 11.…”

“…A53E has been proposed to cause disease by altering α‐synuclein aggregation, and earlier studies showed recombinant A53E α‐synuclein tended to accumulate as oligomers in vitro . We confirmed this property in cells by demonstrating that A53E has an increased tendency to form oligomers compared with WT α‐synuclein.…”

The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

“…Though the mechanisms are poorly understood, all currently known mutations occur in the N-terminal AMP domain (A53T, G46L, G51A, etc.) and result in an autosomal dominant syndrome resembling sporadic PD [17]. The N-terminal domain also contains four repeats with a mitochondrial targeting signal, potentially underscoring the mitochondrial dysfunction seen in PD [17].…”

“…and result in an autosomal dominant syndrome resembling sporadic PD [17]. The N-terminal domain also contains four repeats with a mitochondrial targeting signal, potentially underscoring the mitochondrial dysfunction seen in PD [17]. The second NAC domain is a hydrophobic core strongly associated with α-synuclein aggregation and fibrillization [18].…”