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Synucleinopathies: past, present and future

2016; Wiley; Volume: 42; Issue: 1 Linguagem: Inglês

10.1111/nan.12311

1365-2990

M. G. Spillantini, Michel Goedert,

Ginkgo biloba and Cashew Applications

Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are the most common synucleinopathies. The ordered assembly of α-synuclein leading from a soluble, lipid-bound, to an insoluble, filamentous protein underlies these disorders. Fibrils formed from α-synuclein (Lewy pathology) are seen in brain neurons of more than 95% of patients with PD, and their formation is associated with neurodegeneration. Missense mutations in SNCA, the α-synuclein gene, and multiplications thereof, cause rare cases of PD. Two missense mutations (G51D and A53E) can give rise to neuropathological features reminiscent of both PD and MSA. Sequence variants in the regulatory region of SNCA are associated with increased disease risk. Overexpression of human mutant α-synuclein in animal models causes its ordered assembly and neurodegeneration. α-Synuclein is a 140 amino acid protein that is concentrated in nerve terminals. It binds to lipids through its amino-terminal half, which comprises seven imperfect repeats, and takes on a partly α-helical structure. Under pathological conditions, α-synuclein self-assembles into β-sheet-rich oligomers and fibrils. They assemble from the full-length protein, but only approximately amino acids 30–100 make up the structured part. The related lipid-binding proteins β-synuclein and γ-synuclein are not found in the pathological inclusions of synucleinopathies. Moreover, mouse lines knockout for α-synuclein do not develop neurodegeneration. It follows that synucleinopathies are gain of toxic function, not loss of function, diseases, with the ordered assembly of α-synuclein constituting the gain of toxic function. Close to 200 years ago, James Parkinson published his 1817 monograph entitled 'An Essay on the Shaking Palsy', in which he reported the first detailed clinical description of the disease that Jean-Martin Charcot named after him in 1872. In 1912, Fritz Heinrich Lewy described the inclusions that characterize PD, PDD and DLB in the dorsal motor nucleus of the vagus nerve, the basal nucleus of Meynert, the globus pallidus and the thalamus. In 1919, Konstantin Tretiakoff reported the presence of what he called 'corps de Lewy' (Lewy bodies) in the substantia nigra. He also showed degeneration of the substantia nigra in PD and postulated a connection between nerve cell loss, rigidity and tremor. This discovery followed work by Paul Blocq and Georges Marinesco, who reported a case of parkinsonian tremor caused by a tumour of the substantia nigra. α-Synuclein came to the fore in 1997, when the first genetic cause of PD was identified and the presence of α-synuclein in Lewy bodies and neurites was established in sporadic PD and DLB. The following year, α-synuclein was also shown to be the major component of the filamentous inclusions of MSA (Papp-Lantos bodies). In this special issue of Neuropathology and Applied Neurobiology on synucleinopathies, leading investigators provide an overview of this vibrating field. A basic understanding is at hand and it appears increasingly likely that safe and effective mechanism-based therapies for synucleinopathies will be developed. They will probably be aimed at prevention rather than at treating already existing disease. PD stands out among neurodegenerative diseases, in that an effective symptomatic therapy in the form of dopamine replacement already exists. In the first contribution, Roger Barker and Caroline Williams-Gray provide a comprehensive overview of the clinical features of PD and compare them with those of other synucleinopathies 1. In the second article, Nadia Stefanova and Gregor Wenning focus on the rarer, but more aggressive, MSA, which is divided into parkinsonian (MSA-P) and cerebellar (MSA-C) forms, with many cases having features of both (mixed-type MSA) 2. Autonomic dysfunction is a major feature of MSA. Atypical MSA defines cases of MSA-P and MSA-C that also have frontotemporal dementia, in the apparent absence of autonomic dysfunction. Pathologically, glial cytoplasmic inclusions, besides neuronal inclusions, distinguish MSA from PD, PDD and DLB, where the α-synuclein-positive Lewy pathology is mostly neuronal. It remains to be seen if distinct strains of aggregated α-synuclein give rise to these pathologies. Two silver staining methods, Gallyas-Braak and Campbell-Switzer, distinguish between the α-synuclein inclusions of MSA and PD. The inclusions of MSA are positive with both stains, whereas those of PD are negative with Gallyas-Braak. Clinically, PD and MSA are primarily movement disorders. Nerve cell loss in the pars compacta of the substantia nigra associated with Lewy pathology is the major hallmark of sporadic PD, which is often preceded by non-motor prodromal signs, such as hyposmia, constipation, depression and sleep disorders. Significant cognitive dysfunction is associated more often with PD than with MSA. The prodromal stages of PD may reflect the presence of Lewy pathology outside the substantia nigra. Based on cross-sectional neuroanatomical studies of the presence of Lewy pathology, Braak, Del Tredici and colleagues have suggested that the disease process may start in the gastrointestinal tract, sympathetic ganglia and olfactory bulb, and then spread to the spinal cord, brainstem, substantia nigra and cerebral cortex. In the third article of this special issue, Kelly Del Tredici and Heiko Braak review their and others' findings 3, which are consistent with the spreading of pathology over time. During the past 8 years, much experimental evidence has been adduced to support the prion-like spreading of α-synuclein aggregates. The first strong indication came from PD patients who had received striatal grafts of embryonic neural tissue to replace the function of lost nigral dopaminergic neurons. When these patients died, a decade or more after transplantation, some of the grafted neurons had developed Lewy pathology. In the fourth contribution, Nolwen Rey, Sonia George and Patrik Brundin summarize what is known about the prion-like spreading of aggregated α-synuclein and discuss the methods used to detect seeding and spreading of pathology 4. In PD, the neuronal Lewy pathology appears to form first in nerve terminals, where soluble α-synuclein is located. This may lead to synaptic dysfunction and retrograde degeneration, with nerve cell loss being a later event. In the fifth article, Arianna Bellucci, Nicola Mercuri, Annalena Venneri, Gaia Faustini, Francesca Longhena, Marina Pizzi, Cristina Missale and PierFranco Spano discuss what is known about the physiological function of α-synuclein and its ordered assembly in relation to synaptic loss and connectome dysfunction 5. A major objective behind the identification of novel disease mechanisms is to discover new therapeutic targets. The final contribution by Elvira Valera, Giacomo Compagnoni and Eliezer Masliah discusses novel strategies to treat synucleinopathies, with an emphasis on MSA 6. Aggregation of α-synuclein and chaperones that influence its aggregation are important targets, as the ordered assembly of α-synuclein constitutes the gain of toxic function that underlies synucleinopathies. The ordered assembly of proteins associated with neurodegenerative diseases, be they Aβ, tau or α-synuclein, is concentration dependent. Reduced production and increased clearance of α-synuclein are therefore valid targets for therapy. Besides its cell autonomous effects, a reduction in cytosolic α-synuclein is also likely to reduce intercellular propagation, which has emerged as an important contributor to disease pathogenesis. Immunotherapy and degradation by extracellular proteases may target the intercellular transfer of α-synuclein aggregates directly. The process underlying sporadic synucleinopathies may originate in localized portions of the nervous system. What predisposes certain brain regions and cell types to the assembly of α-synuclein into oligomers and filaments is unknown. Could somatic SNCA mutations play a role? Unlike dominantly inherited forms of synucleinopathies, where half of the expressed α-synuclein molecules are either mutant or overexpressed, most cells express normal levels of wild-type protein in sporadic cases of disease. In these cases, the early events may be followed by the more deterministic spreading of pathology, which will eventually give rise to disease symptoms. The long preclinical phase of synucleinopathies augurs well for the development of therapies.