- Synucleinopathy refers to a group of progressive neurodegenerative disorders characterized by the abnormal accumulation and aggregation of the protein alpha-synuclein in the nervous system. This misfolded protein tends to accumulate inside neurons and glial cells, forming pathological inclusions that disrupt normal cellular function and ultimately lead to cell death. The term encompasses several major diseases, including Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and Multiple system atrophy (MSA), each with distinct clinical features but united by a shared pathological hallmark: alpha-synucleinopathy.
- Alpha-synuclein is a presynaptic neuronal protein that plays a role in synaptic vesicle regulation and neurotransmitter release, particularly dopamine. Under normal conditions, it exists in a soluble and unstructured form. However, in synucleinopathies, alpha-synuclein undergoes misfolding and aggregates into insoluble fibrils that form the core of Lewy bodies (in PD and DLB) or glial cytoplasmic inclusions (in MSA). These protein aggregates interfere with various cellular processes, including mitochondrial function, protein degradation pathways (like the ubiquitin-proteasome system), and axonal transport.
- Each form of synucleinopathy has distinctive patterns of pathology and clinical presentation. In Parkinson’s disease, alpha-synuclein accumulates primarily in dopaminergic neurons of the substantia nigra, leading to the characteristic motor symptoms of bradykinesia, rigidity, tremor, and postural instability. In Dementia with Lewy bodies, alpha-synuclein inclusions are more widely distributed in cortical areas, leading to cognitive impairment, visual hallucinations, and fluctuating attention, often alongside parkinsonism. Multiple system atrophy, in contrast, involves alpha-synuclein accumulation predominantly in oligodendroglial cells, contributing to a combination of autonomic failure, cerebellar ataxia, and parkinsonian features.
- The pathogenesis of synucleinopathies remains an active area of research. Although the exact triggers for alpha-synuclein misfolding are not fully understood, several factors have been implicated, including genetic mutations (e.g., in SNCA, LRRK2, or GBA genes), oxidative stress, inflammation, and impaired cellular clearance mechanisms. Evidence also suggests that misfolded alpha-synuclein may spread from cell to cell in a prion-like manner, contributing to the progression of pathology across the brain.
- Diagnosis of synucleinopathies is primarily clinical, supported by neuroimaging and sometimes cerebrospinal fluid biomarkers, although definitive confirmation currently relies on post-mortem neuropathological examination. Because these disorders often overlap with other neurodegenerative diseases, accurate diagnosis can be challenging, especially in early stages.
- There are currently no disease-modifying treatments for synucleinopathies. Therapies are largely symptomatic, targeting motor or cognitive symptoms and associated complications. For instance, levodopa is used to manage motor symptoms in PD and some MSA patients, while cholinesterase inhibitors may help with cognitive decline in DLB. Research efforts are focused on developing strategies to reduce alpha-synuclein aggregation, enhance its clearance, and block its propagation across neurons and glial cells.
