Elsevier

The Lancet Neurology

Volume 10, Issue 11, November 2011, Pages 1015-1025
The Lancet Neurology

Review
Pathological roles of α-synuclein in neurological disorders

https://doi.org/10.1016/S1474-4422(11)70213-7Get rights and content

Summary

Substantial genetic, neuropathological, and biochemical evidence implicates the presynaptic neuronal protein α-synuclein in Parkinson's disease and related Lewy body disorders. How dysregulation of α-synuclein leads to neurodegeneration is, however, unclear. Soluble oligomeric, but not fully fibrillar, α-synuclein is thought to be toxic. The major neuronal target of aberrant α-synuclein might be the synapse. The effects of aberrant α-synuclein might include alteration of calcium homoeostasis or mitochondrial fragmentation and, in turn, mitochondrial dysfunction, which could link α-synuclein dysfunction to recessive and toxin-induced parkinsonism. α-Synuclein also seems to be linked to other genetic forms of Parkinson's disease, such as those linked to mutations in GBA or LRRK2, possibly through common effects on autophagy and lysosomal function. Finally, α-synuclein is physiologically secreted, and this extracellular form could lead to the spread of pathological accumulations and disease progression. Consequently, factors that regulate the levels, post-translational modifications, specific aberrant cellular effects, or secretion of α-synuclein might be targets for therapy.

Introduction

α-Synuclein is an abundant 140-residue neuronal protein, that, under physiological conditions, is found mainly in neuronal presynaptic terminals, close to synaptic vesicles. It is a member of a conserved family of proteins that also includes β-synuclein and γ-synuclein, and was originally described as the precursor protein for the non-amyloid component of Alzheimer's disease senile plaques.1 The protein is intrinsically unfolded, which means that in the purified form at neutral pH it lacks an ordered secondary or tertiary structure. Upon binding to membranes or synthetic vesicles containing acidic phospholipids, however, it assumes an α-helical structure.2 Although its exact functions are unknown, α-synuclein is assumed to help in the regulation of synaptic-vesicle release and to provide a stabilising effect on complexes of SNARE family proteins.3, 4, 5, 6 Three missense point mutations (Ala53Thr, Ala30Pro, and Glu46Lys) and multiplications of the gene locus have been identified in SNCA, which encodes α-synuclein, in families with autosomal dominant Parkinson's disease (PD).7 Importantly, genome-wide association studies have shown clearly that SNCA is also linked to sporadic PD,8 and indicate a possible link to multiple system atrophy.9

Deposits of α-synuclein have been identified in pathological aggregates, such as Lewy bodies, Lewy neurites, and oligodendroglial inclusions in patients with PD and several other neurodegenerative disorders, such as dementia with Lewy bodies and multiple system atrophy.10 These disorders are termed synucleinopathies. In dementia with Lewy bodies, in which dementia and motor deficits are linked closely in time, accumulation of α-synuclein is seen throughout the brain, including the cortex. In multiple system atrophy, which can involve extrapyramidal, cerebellar, pyramidal, and autonomic dysfunction, the predominant pathological feature is oligodendroglial α-synuclein inclusions. Other neurological disorders, including Alzheimer's disease and neurodegeneration with brain iron accumulation, can also manifest with abnormal α-synuclein deposition, and can thus be viewed as being within the range of synucleinopathies.

Abnormal deposition of α-synuclein occurs early in the disease process, at least in PD, and seems to follow a sequence of ascension from lower brainstem centres to limbic and wide cortical association areas.11 The more widespread accumulation of α-synuclein is thought to underlie, at least in part, the cognitive and behavioural deficits in PD with dementia. The mechanisms that underlie the aberrant functions of α-synuclein and how these impact on disease pathogenesis remain poorly understood, but some possibilities have been suggested. In this Review we focus on such pathogenic pathways in neurological disorders and highlight recent developments and potential links to other genetic defects associated with PD, which is the most common pure synucleinopathy.

Section snippets

Concentration-dependent α-synuclein oligomerisation and aggregation

Recombinant α-synuclein incubated under certain conditions in vitro assumes an oligomeric conformation and is gradually converted to β-sheet-rich, fibrillar structures that resemble the Lewy bodies and neurites found in human neuropathological samples. This process is termed aggregation and is thought to underlie the toxic potential of α-synuclein.2 In transgenic mice overexpressing human α-synuclein, coexpression of β-synuclein, the non-amyloidogenic homologue of α-synuclein, inhibits

Lysosomal involvement and the role of glucocerebrosidase

Lysosomes degrade α-synuclein but lysosomal function also seems to be affected by α-synuclein in a way that leads to neurotoxic effects. The PD-linked Ala53Thr and Ala30Pro mutations and modification of the wild-type protein by dopamine inhibit chaperone-mediated autophagy and, therefore, prevent the degradation of related substrates.34, 37, 40, 41 The neuronal survival factor MEF2D might be an especially relevant substrate.42 Inhibition of chaperone-mediated autophagy through aberrant

Mitochondrial involvement and recessive parkinsonism

Mitochondrial alterations are well recognised in PD. Data that suggest a relation between the pathobiology of α-synuclein and damage to this organelle are, therefore, of interest. Endogenous α-synuclein is detected within rodent brain mitochondria, especially in the outer mitochondrial membrane.57, 58, 59 Some studies, one of which was in patients with PD,60 have shown α-synuclein accumulation within the inner mitochondrial membrane, dependent on the N-terminal membrane-binding domain.59, 60, 61

α-Synuclein, LRRK2, tau, and cytoskeletal effects

Genome-wide association studies have identified strong associations with PD for SNCA, MAPT (which encodes microtubule-associated protein tau), and LRRK2.8 The identification of these genes in such analyses does not necessarily mean that their protein products interact synergistically or otherwise to facilitate the pathogenesis of PD. Functional links might, however, exist between the proteins that affect the cytoskeleton. Oligomerisation of α-synuclein could destabilise cytoskeletal units,

Effects on neurotransmitter release and calcium homoeostasis

Data largely derived from α-synuclein knockout mice suggest that α-synuclein normally mediates negative control of neurotransmitter release and has a possible role in assembly of SNARE family complexes.3, 4, 5, 6 Whether these apparently physiological functions at the presynaptic terminal contribute to the pathogenic effects of α-synuclein has been investigated.

Iwai and colleagues86 showed abnormal localisation of the protein in presynaptic terminals. The researchers suggested that this

α-Synuclein secretion and disease propagation

α-Synuclein has no endoplasmic reticulum signal peptide and was thought at first to be an exclusively intracellular protein. This notion was challenged when α-synuclein was detected in biological fluids, such as blood plasma and CSF.107, 108 Furthermore, α-synuclein could be secreted in the culture medium of neuronal cells independent of whether stable overexpression,108 inducible overexpression,109 transient transfection,110, 111 or viral-mediated expression112 was used.

The mechanism of

Conclusions

Aberrant expression of α-synuclein can lead to multiple intracellular and potentially extracellular pathogenetic effects. The mechanisms involved, especially feed-forward amplification loops, might be amenable to therapeutic interventions, although, in view of the range of toxic effects of α-synuclein, the inhibition of neurodegeneration is likely to be incomplete. The discovery of a common denominator for the harmful effects that could be effectively targeted would be most useful.

Search strategy and selection criteria

We searched PubMed for original reports and reviews published in peer-reviewed journals, with the search terms “alpha-synuclein”, “neurodegeneration”, “Parkinson's disease”, “lysosomes”, “synapse”, and “secretion”. Although we set no parameters for years of publication, most of the original research we used to support this Review was published from January, 1993, to August, 2011; we also selected the most recent reviews from leaders in the subject.

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