Synucleinopathies

Synucleinopathies are neurodegenerative disorders characterized by abnormal accumulation of alpha-synuclein. Misfolded alpha-synuclein forms neuronal Lewy bodies and neurites, and glial inclusions in oligodendrocytes in multiple system atrophy. The distribution of these inclusions shapes clinical features and progression.

The best known synucleinopathies are Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). PD and DLB share alpha-synuclein pathology but differ in dominant symptoms and dementia timing. REM sleep behavior disorder and other non-motor features often presage motor symptoms.

Pathophysiology: Misfolded alpha-synuclein aggregates in neural networks with prion-like spread. In PD and DLB, neuronal inclusions affect nigrostriatal pathways, causing motor symptoms and non-motor features. In MSA, aggregates accumulate in oligodendroglia, producing autonomic failure, parkinsonism, and cerebellar ataxia.

Genetics and risk factors: Rare familial cases link to SNCA with multiplications or mutations; variants in GBA and LRRK2 are risk factors for PD and DLB. Most synucleinopathies are sporadic. Aging is the main risk factor; environmental influences are not well understood.

Diagnosis and treatment: Diagnosis is clinical, supported by imaging and biomarkers when available. There is no disease-modifying therapy; management is symptomatic. PD is treated with levodopa and other dopaminergic agents, plus treatment of non-motor symptoms. DLB and MSA require tailored approaches addressing autonomic and cognitive symptoms, with fall prevention and multidisciplinary care.

Research directions include therapies targeting alpha-synuclein aggregation and propagation, among immunotherapies and small molecules. Biomarkers and imaging aim to enable earlier and more accurate diagnosis and monitoring of progression.