Alpha Synuclein: Expression, physiologic function, and interacting molecules

a-Syn is a 140-amino-acid protein identified as a hallmark constituent of Lewy bodies present in a group of neurodegenerative diseases, including PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and diffuse Lewy
body disease (DLBD). Despite the implication of nuclear localization in the nomenclature, a-syn is primarily localized to presynaptic terminals in the central
nervous system (CNS) and is abundant in brain areas rich in synaptic vesicles and associated with synaptic plasticity, such as the hippocampus, cerebral cortex, and amygdala. Early studies in songbirds (Zebra finch) demonstrate a role for a-syn in synaptic plasticity and that song learning coincides with the upregulation of a-syn mRNA. The physiologic function of a-syn in normal brain is poorly understood.
a-Syn may play a role in neuronal differentiation, regulation of dopamine release, regulation of cell viability, modulation of synaptic transmission, and vesicular recycling. Additional roles in cell adhesion, development, regulation of dopamine uptake, and vesicle transport in neurons are described.

As a highly abundant neuronal protein in the mammalian brain, a-syn interacts with a number of proteins: acting as a high-affinity inhibitor of phospholipase D2, as a regulator for certain enzymes, transporters, and neurotransmitter vesicles, promoting oxidative stress, and as a regulator for the MAP kinase pathway by forming a complex with transcription factor Elk. a-Syn also plays a role in modulating the architecture of membrane lipid components by associating with lipid membranes, fatty acids, detergent micelles, lipid rafts, and lipid droplets. Metal ions such as Cu2þ and potentially Fe2+, Al3+, Zn2+, Mg2+, Ca2+, Co2+, Fe3+, Tb3+ and Mn2+ interact with a-syn, although a-syn is not widely regarded as a traditional metalloprotein. a-Syn also displays characteristics of chaperone-like proteins and interacts with a family of ubiquitous cytoplasmic chaperones including 14-3-3 proteins, in addition to other abundant proteins like protein kinase C (PKC), the bcl-2 homologue
BAD, and extracellular regulated kinase (ERK).

The endogenous function of a-syn has not been clearly delineated through characterization of mice deficient in a-syn expression. The first reports of mice deficient in a-syn demonstrated normal synaptic architecture and brain morphology
that led to slight changes in synaptic transmission. Additional laboratories have generated a-syn–knockout mice in combination with knockout of the two other synuclein family members in mammals, b-synuclein and g-synuclein, with little
to no apparent phenotype. A reproducible phenotype for mice deficient in a-syn includes heightened resistance to the neurotoxin MPTP. MPTP, specifically
MPP+ generated by MAO-B activity, targets susceptible dopaminergic neurons and can inhibit mitochondrial complex I activity, although the importance of mitochondrial inhibition in initiating cell death remains in question. Because the exact mechanism of MPTP action in neurons is not clear, inferring a-syn function via MPTP resistance
becomes difficult. The implication that cells containing a-syn may be more susceptible to environmentally derived toxins is provocative, but mice overexpressing a-syn may not be more susceptible to MPTP, and, in some cases, are
protected against neuronal toxins like paraquat. One explanation may involve the lack of functional overlap between mouse a-syn and human a-syn in neurons.

Clear orthologues to a-syn may not exist in lower organisms and invertebrates that would serve as models for study, further hindering efforts to understand the normal function of a-syn in cells. If native a-syn function is important for pathogenesis
and that associated function is largely unknown, inserting a-syn into organisms that are normally devoid of the protein without the ability to assess whether a-syn integrates properly into the cell would produce a model system difficult
to interpret. a-Syn function may modify crucial physiologic events in mammalian neurons that necessitate high redundancy from other proteins. Conversely, a-syn may play a more generalized role as a dispensable cofactor for a number of diverse cellular pathways present in higher organisms. The lack of a clearly described role for a-syn in cells negatively affects viability as a therapeutic target, because alteration or disruption of a-syn in humans may produce unanticipated
and deleterious side effects that outweigh potential benefits.