Synucleinopathies can overlap with tauopathies, possibly because of interaction between the synuclein and tau proteins.[4]
REM sleep behavior disorder (RBD) is a parasomnia in which individuals with RBD lose the paralysis of muscles (atonia) that is normal during rapid eye movement (REM) sleep, and act out their dreams or have other abnormal movements or vocalizations.[5] Abnormal sleep behaviors may appear decades before any other symptoms, often as an early sign of a synucleinopathy.[6] On autopsy, 94 to 98% of individuals with polysomnography-confirmed RBD are found to have a synucleinopathy—most commonly DLB or PD.[5][7][8] Other symptoms of the specific synucleinopathy usually manifest within 15 years of the diagnosis of RBD,[9] but may emerge up to 50 years after RBD diagnosis.[5]
Alpha-synuclein deposits can affect the cardiac muscle and blood vessels.[10] Almost all people with synucleinopathies have cardiovascular dysfunction, although most are asymptomatic.[10]
From chewing to defecation, alpha-synuclein deposits affect every level of gastrointestinal function. Symptoms include upper gastrointestinal tract dysfunction such as delayed gastric emptying or lower gastrointestinal dysfunction, such as constipation and prolonged stool transit time.[10]
The pathological aggregation of alpha-synuclein plays a key role in neurodegenerative disease.[11] The misfolding and aggregation of alpha-synuclein form toxic fibrils, which in turn form pathological inclusions, such as Lewy bodies.[12] These protein deposits are a hallmark of synucleinopathies, and may interrupt crucial neuronal processes, such as functions of synaptic vesicles, leading to neuronal death.[11] Alpha-synuclein is encoded by the SNCAgene, and a mutation in this gene can lead to dysfunctions of the protein structure.[13]
Post-translational modifications are also implicated in the aggregation of alpha-synuclein, mostly occurring in the C-terminus. Phosphorylation, acetylation, ubiquitination, oxidation, and other modifications alter the structure and charge of alpha-synuclein, which can in turn lead to the formation of Lewy bodies.[14]
Alpha-synuclein has a prion-like molecular spread and is suggested to be released through rare exocytosis pathways.[14] This release with exosomes on their way to degradation in lysosomes suggest this process may be calcium-dependent, and therefore suggests propagation of misfolded alpha-synuclein between neurons synaptically connected.[14] Neuronal death caused by aggregated alpha-synuclein may also further accelerate the formation of these toxic aggregates, which can then trigger a selective progression of neuronal death through impairment of the mitochondria, alteration of calcium homeostasis, and lysosomal dysfunction. [13][15]
Early synaptic and plastic alterations mediated by alpha-synuclein, as well as the mechanisms of inflammation and synaptic dysfunction that occurs before neurodegeneration, are of key interest for investigating possible therapies for synucleinpathies.[15]
Diagnosis
Differential diagnosis
Persons with PD are typically less caught up in their visual hallucinations than those with DLB.[16] There is a lower incidence of tremor at rest in DLB than in PD, and signs of parkinsonism in DLB are more symmetrical.[6] In MSA, autonomic dysfunction appears earlier and is more severe, and is accompanied by uncoordinated movements, while visual hallucinations and fluctuating cognition are less common than in DLB.[17] Urinary difficulties are one of the earliest symptoms with MSA, and are often severe.[10]
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