Fariha Jamal is an Assistant Professor, Department of Neurology, Baylor College of Medicine and an Assistant Clinical Director at the Parkinson’s Disease Research Education and Clinical Center, Michael E. DeBakey VA Medical Center in Houston, Texas. Correspondence: Fariha Jamal (fariha.zaheer@bcm.edu)
Author Disclosures The author reports no actual or potential conflicts of interest with regard to this article.
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α-synuclein is a small 140 amino-acid protein with a N-terminal region that can interact with cell membranes and a highly acidic unstructured C-terminal region.6 α-synuclein is physiologically present in the presynaptic terminals of neurons and involved in synaptic plasticity and vesicle trafficking.7 There are different hypotheses about the native structure of α-synuclein. The first suggests that it exists in tetrameric form and may be broken down to monomer, which is the pathogenic form of α-synuclein. The second hypothesis suggests that it exists primarily in monomeric form, whereas other studies have shown that both forms exist and with pathologic changes, monomer accumulates in abundance and is neurotoxic.8-11 Work by Burré and colleagues shows that native α-synuclein exists in 2 forms: a soluble, cytosolic α-synuclein, which is monomeric, and a membrane-bound multimeric form.12,13
Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.14,15 Pathologic α-synuclein exists in insoluble forms that can aggregate into oligomers and fibrillar structures.16 Lysosomal dysfunction may promote accumulation of insoluble α-synuclein. Prior work has shown that several degradation pathways in lysosomes, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, are down regulated, thus contributing to the accumulation of abnormal α-synuclein.17,18 Accumulation of pathologic α-synuclein leads to mitochondrial dysfunction in PD animal models, contributing further to neurotoxicity.19,20 Aggregates of phosphorylated α-synuclein have been demonstrated in dementia with Lewy body.21
In addition, α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein.22 Previous work in animal models suggested a prion proteinlike spread of α-synuclein.23 This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.24
It has been proposed that α-synuclein accumulation and extracellular release initiates an immune response that leads to activation of microglia. This has been shown in PD animal models, overexpressing α-synuclein. In 2008 Park and colleagues demonstrated that microglial activation is enhanced by monomeric α-synuclein, not by the aggregated variant.25 Other studies have reported activated microglia around dopaminergic cells in substantia nigra.26 Sulzer and colleagues showed that peptides from α-synuclein can act as antigens and trigger an autoimmune reaction via T cells.27 PD may be associated with certain HLA-haplotypes.28 In other words, α-synuclein can induce neurodegeneration via different mechanisms, including alteration in synaptic vesicle transmission, mitochondrial dysfunction, neuroinflammation, and induction of humoral immunity.
Immunization
Due to these observations, there had been huge interest in developing antibody-based therapies for PD. A similar approach had been tested in Alzheimer disease (AD). Intracellular tangles of tau protein and extracellular aggregates of amyloid are the pathologic substrates in AD. Clinical trials utilizing antibodies targeting amyloid showed reduction in abnormal protein accumulation but no significant improvement in cognition.29 In addition, adverse events (AEs), such as vasogenic edema and intracerebral hemorrhage, were reported.30 Careful analysis of the data suggested that inadequate patient selection or targeting only amyloid, may have contributed to unfavorable results.31 Since then, more recent clinical trials have focused on careful patient selection, use of second generation anti-amyloid antibodies and immunotherapies targeting tau.32
