Synucleinopathy: Difference between revisions – Wikipedia

 

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Alpha-synuclein has a [[Prion|prion-like]] molecular spread and is suggested to be released through rare exocytosis pathways.<ref name=”:2″ /> This release with [[Exosome (vesicle)|exosomes]] on their way to degradation in [[Lysosome|lysosomes]] suggest this process may be calcium-dependent, and therefore suggests propagation of misfolded alpha-synuclein between neurons synaptically connected.<ref name=”:2″ /> 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 [[Mitochondrion|mitochondria]], alteration of [[Calcium metabolism|calcium homeostasis]], and lysosomal dysfunction. <ref name=”:12″>{{Cite journal |last=Yaribash |first=Shakila |last2=Mohammadi |first2=Keyhan |last3=Sani |first3=Mahmood Alizadeh |date=2025-03-26 |title=Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson’s Disease |url=https://link.springer.com/10.1007/s10571-025-01544-2 |journal=Cellular and Molecular Neurobiology |language=en |volume=45 |issue=1 |doi=10.1007/s10571-025-01544-2 |issn=1573-6830 |pmc=11947388 |pmid=40140103}}</ref><ref name=”:3″>{{Cite journal |last=Calabresi |first=Paolo |last2=Mechelli |first2=Alessandro |last3=Natale |first3=Giuseppina |last4=Volpicelli-Daley |first4=Laura |last5=Di Lazzaro |first5=Giulia |last6=Ghiglieri |first6=Veronica |date=2023-03-01 |title=Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction |url=https://www.nature.com/articles/s41419-023-05672-9 |journal=Cell Death & Disease |language=en |volume=14 |issue=3 |pages=176 |doi=10.1038/s41419-023-05672-9 |issn=2041-4889}}</ref>

Alpha-synuclein has a [[Prion|prion-like]] molecular spread and is suggested to be released through rare exocytosis pathways.<ref name=”:2″ /> This release with [[Exosome (vesicle)|exosomes]] on their way to degradation in [[Lysosome|lysosomes]] suggest this process may be calcium-dependent, and therefore suggests propagation of misfolded alpha-synuclein between neurons synaptically connected.<ref name=”:2″ /> 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 [[Mitochondrion|mitochondria]], alteration of [[Calcium metabolism|calcium homeostasis]], and lysosomal dysfunction. <ref name=”:12″>{{Cite journal |last=Yaribash |first=Shakila |last2=Mohammadi |first2=Keyhan |last3=Sani |first3=Mahmood Alizadeh |date=2025-03-26 |title=Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson’s Disease |url=https://link.springer.com/10.1007/s10571-025-01544-2 |journal=Cellular and Molecular Neurobiology |language=en |volume=45 |issue=1 |doi=10.1007/s10571-025-01544-2 |issn=1573-6830 |pmc=11947388 |pmid=40140103}}</ref><ref name=”:3″>{{Cite journal |last=Calabresi |first=Paolo |last2=Mechelli |first2=Alessandro |last3=Natale |first3=Giuseppina |last4=Volpicelli-Daley |first4=Laura |last5=Di Lazzaro |first5=Giulia |last6=Ghiglieri |first6=Veronica |date=2023-03-01 |title=Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction |url=https://www.nature.com/articles/s41419-023-05672-9 |journal=Cell Death & Disease |language=en |volume=14 |issue=3 |pages=176 |doi=10.1038/s41419-023-05672-9 |issn=2041-4889}}</ref>

Early synaptic and [[Neuroplasticity|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.<ref name=”:32″>{{Cite journal |last=Calabresi |first=Paolo |last2=Mechelli |first2=Alessandro |last3=Natale |first3=Giuseppina |last4=Volpicelli-Daley |first4=Laura |last5=Di Lazzaro |first5=Giulia |last6=Ghiglieri |first6=Veronica |date=2023-03-01 |title=Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction |url=https://www.nature.com/articles/s41419-023-05672-9 |journal=Cell Death & Disease |language=en |volume=14 |issue=3 |pages=176 |doi=10.1038/s41419-023-05672-9 |issn=2041-4889}}</ref>

==Diagnosis==

==Diagnosis==

Medical condition

Synucleinopathy
Other names	α-Synucleinopathies
Positive α-Synuclein staining of a Lewy body in a patient with Parkinson’s disease.
Specialty	Neurology

Synucleinopathies (also called α-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells.^[1] The synucleinopathies include Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).^[1] Other rare disorders, such as various neuroaxonal dystrophies, also have α-synuclein pathologies.^[2]

The synucleinopathies have shared features of parkinsonism, impaired cognition, sleep disorders, and visual hallucinations.^[3]

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]

Urinary retention, waking at night to urinate, increased urinary frequency and urgency, and over- or underactive bladder are common in people with synucleinopathies.^[10] Sexual dysfunction usually appears early in synucleinopathies, and may include erectile dysfunction, and difficulties achieving orgasm or ejaculating.^[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 pathological hallmark of synucleinopathies, and may interrupt crucial neuronal processes, such as functions of synaptic vesicles, leading to neuronal death.^[13] Alpha-synuclein is encoded by the SNCA gene, and a mutation in this gene can lead to dysfunctions of the protein structure.^[14]

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.^[15]

Alpha-synuclein has a prion-like molecular spread and is suggested to be released through rare exocytosis pathways.^[15] 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.^[15] 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. ^[16][17]

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.^[18]

Persons with PD are typically less caught up in their visual hallucinations than those with DLB.^[19] 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.^[20] Urinary difficulties are one of the earliest symptoms with MSA, and are often severe.^[10]