The role of α-synuclein in neurodegeneration — An update

Abstract

Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

Cerebral glucose metabolism and cognition in newly diagnosed Parkinson's disease: ICICLE-PD study

“…In AD, glucose hypometabolism is a relatively early feature, preceding cortical atrophy, and predicting cognitive decline at an early stage 11. In PD, this region shows reduced FDG and blood flow in the absence of atrophy,5 26 suggesting that in PD also, reduced metabolism is a relatively early feature, possibly reflecting synaptic dysfunction due to local α-synuclein pathology,27 28 which precedes atrophy and cognitive decline.…”

Asiatic Acid Prevents Oxidative Stress and Apoptosis by Inhibiting the Translocation of α-Synuclein Into Mitochondria

“…Parkinson disease (PD) is a progressive neurodegenerative disorder that is characterized by the preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc)( Moore et al, 2005 ) and the formation of intracytoplasmic protein aggregates, termed Lewy bodies, a major component of which is α-synuclein (α-syn) ( Spillantini et al, 1997 ). Increased expression of α-syn has been hypothesized to cause familial and sporadic PD, culminating in a loss of nigrostriatal dopaminergic neurons and motor deficits ( Feany and Bender, 2000 ; Rochet et al, 2004 ; Lee and Trojanowski, 2006 ; Jellinger, 2012 ).…”

What’s to like about the prion-like hypothesis for the spreading of aggregated α-synuclein in Parkinson disease?

“…Of course this interplay on its own could explain neurodegeneration in the PD brain 4 . However, it does not fully explain the slow degeneration associated with the disease.…”

“…In other forms of PD α-syn might promote an immune response in at least one of two ways. Either α-syn secreted into the extracellular space could stimulate microglia directly, 4 or by causing neuronal death, misfolded α-syn might indirectly cause microglial activation 46 …”

“…α-Syn is a 140 amino acid protein of predominantly presynaptic localization in neurons, although it is ubiquitously expressed 2 , 4 . The protein is comprised of 3 domains, (1) an N-terminal lipid binding α-helix, (2) a non-amyloidß component (NAC) domain and (3) an unstructured C-terminus.…”