Clinical overview of the synucleinopathies

Abstract

The term synucleinopathies is used to name a group of neurodegenerative disorders characterized by fibrillary aggregates of alpha-synuclein protein in the cytoplasm of selective populations of neurons and glia. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA). Clinically, they are characterized by a chronic and progressive decline in motor, cognitive, behavioural, and autonomic functions, depending on the distribution of the lesions. Because of clinical overlap, differential diagnosis is sometimes very difficult. Parkinsonism is the predominant symptom of PD, but it can be indistinguishable from the parkinsonism of DLB and MSA. Autonomic dysfunction, which is an isolated finding in PAF, may be present in PD and DLB, but is usually more prominent and appears earlier in MSA. DLB could be the same disease as PD but with widespread cortical pathological states, leading to dementia, fluctuating cognition, and the characteristic visual hallucinations. The deposition of aggregates of synuclein in neurons and glia suggests that a common pathogenic mechanism may exist for these disorders. Even though synuclein may play an important role in disease development in these disorders, in light of the different symptom complex and prognosis and management issues that characterize each disorder, we think that the term synucleinopathy has little practical value as a diagnostic term for the clinician. Clinicians should attempt to reach standard clinical diagnosis on patients, such as PD, PAF, or MSA.

Regulation of α-Synuclein Expression in Limbic and Motor Brain Regions of Morphine-Treated Mice

“…␣-Synuclein has long been associated with neurodegeneration. It is prone to form oligomers, fibrillize, and precipitate, which leads to the production of intracellular inclusions, such as Lewy bodies, characteristic of Parkinson's disease and other neurodegenerative disorders, called synucleinopathies (Spillantini et al, 1997;Marti et al, 2003;Vekrellis et al, 2004). Although the formation of ␣-synuclein oligomers and fibrils may require special conditions that are prerequisites for neurodegenerative pathologies, some studies suggest that the overexpression of ␣-synuclein is sufficient to produce major cellular toxicity, particularly in dopaminergic neurons (Hsu et al, 2000;Saha et al, 2000;Lotharius and Brundin, 2002).…”

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

“…In particular, inclusions, known as Lewy bodies, are detected within the neuronal tissue of patients with Parkinson's disease and dementia with Lewy bodies. These inclusions are composed primarily of the intrinsically disordered protein, α-synuclein (α-syn) (22). The aggregation of soluble proteins to form amyloid fibrils is well established to involve a nucleation-dependent polymerisation reaction (23).…”

Small Heat-shock Proteins Prevent α-Synuclein Aggregation via Transient Interactions and Their Efficacy Is Affected by the Rate of Aggregation

“…The deposition of fibrillar ␣-syn into inclusion bodies, known as Lewy bodies or Lewy neurites when they are present in the cell body or processes, respectively, is a pathological hallmark of a number of neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, collectively referred to as the ␣-synucleinopathies (8). Moreover, multiplication of SNCA, which encodes for ␣-syn, or missense mutations (A53T, A30P, and E46K) in this gene, cause familial early-onset Parkinson's disease (9 -11).…”