What is alpha‑synuclein, how does it contribute to Parkinson disease, dementia with Lewy bodies, and multiple system atrophy, and are there any diagnostic tests or disease‑modifying therapies that target it?

Alpha-Synuclein in Neurodegenerative Disease

What is Alpha-Synuclein?

Alpha-synuclein is a 140-amino acid neuronal protein that predominantly localizes to presynaptic terminals and serves as the primary pathological component of Lewy bodies in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. 1, 2

• Alpha-synuclein is a natively unfolded protein that can transiently bind lipid membranes and acquire partial alpha-helical conformation under physiological conditions 3
• The protein is highly abundant in the brain and plays regulatory roles in synaptic vesicle trafficking, including exocytosis, endocytosis, and neurotransmitter release 2
• Under pathological conditions, alpha-synuclein misfolds and aggregates to form oligomers, protofibrils, and insoluble fibrils with increased beta-sheet configuration 4, 3

Pathological Mechanisms in Specific Diseases

Parkinson's Disease

In Parkinson's disease, alpha-synuclein forms neuronal Lewy bodies predominantly composed of alpha-synuclein and ubiquitin, following a predictable anatomical progression pattern. 5

• Lewy body deposition initially involves the medulla oblongata, pontine tegmentum, and olfactory system 5, 1
• Later involvement occurs in the substantia nigra and other deep gray nuclei, corresponding to the onset of clinical motor symptoms 5
• Final stages show cortical deposition of Lewy bodies 5
• Clinical symptoms emerge after approximately 40-50% of dopaminergic neurons in the substantia nigra have been lost, roughly 5 years after initial neuronal degeneration begins 5

Dementia with Lewy Bodies

Dementia with Lewy bodies is characterized by neocortical (diffuse) distribution of alpha-synuclein pathology, with Lewy bodies and alpha-synuclein-immunoreactive neurites throughout cortical regions. 1, 4

• The neocortical (diffuse) pattern of Lewy body disease provides an adequate neuropathological explanation for dementia in DLB 6, 1
• Brainstem-predominant Lewy body disease with cognitive impairment should prompt consideration of other contributing pathologies 6, 1
• Co-existent amyloid pathology is common, occurring in up to 63% of individuals older than 80 years with DLB 6

Multiple System Atrophy

Multiple system atrophy differs from Parkinson's disease and dementia with Lewy bodies by featuring abnormal cytoplasmic inclusions of alpha-synuclein and ubiquitin specifically in oligodendroglia rather than neurons. 5, 7

• MSA is classified as a synucleinopathy but with a distinct cellular distribution pattern compared to other Lewy body disorders 5
• Alpha-synuclein forms the major component of the filamentous inclusions in MSA, establishing an unexpected pathological link between MSA and Lewy body disorders 7
• This finding establishes that alpha-synucleinopathies constitute a major class of human neurodegenerative disorders 7

Diagnostic Testing for Alpha-Synuclein Pathology

Neuropathological Classification

Immunohistochemical detection of alpha-synuclein is the preferred and essential method for identifying Lewy bodies, providing greater sensitivity than standard hematoxylin and eosin staining. 1

• Lewy body disease can be classified into five categories based on alpha-synuclein distribution: none, brainstem-predominant, limbic (transitional), neocortical (diffuse), or amygdala-predominant 1
• This classification system is essential for neuropathological assessment of Lewy body diseases 1

Clinical Imaging Biomarkers (Indirect Assessment)

DaTscan (I-123 Ioflupane SPECT) demonstrates reduced dopamine-transporter uptake in the striatum with loss of normal comma-shaped appearance in the putamina, achieving 78% sensitivity and 90% specificity for detecting synucleinopathies. 6

• DaTscan shows decreased dopamine transporter uptake in both Parkinson's disease and dementia with Lewy bodies, but normal uptake in Alzheimer's disease 6
• FDG-PET reveals occipital hypometabolism in Lewy body disorders, differentiating them from Alzheimer's disease 6
• The "cingulate island sign" (preservation of FDG uptake in posterior cingulate gyrus despite occipital hypometabolism) serves as a biomarker favoring Lewy body dementia 6
• MRI shows relative preservation of medial temporal lobe and hippocampi in Lewy body dementia, contrasting with marked atrophy in Alzheimer's disease 6

Critical Diagnostic Pitfall

Do not use amyloid PET/CT alone to differentiate Lewy body disorders from Alzheimer's disease, as co-existent amyloid pathology is extremely common in synucleinopathies. 6

• The Society of Nuclear Medicine advises that brain amyloid PET/CT is rarely appropriate in patients with suspected Lewy body dementia 6
• Mixed neuropathology is the rule rather than the exception, with up to 50-60% of dementia cases having multiple contributing proteinopathies 5, 6

Disease-Modifying Therapies Targeting Alpha-Synuclein

Currently, no disease-modifying therapies targeting alpha-synuclein are approved for clinical use, though this remains an active area of investigation. The provided evidence does not contain information about approved alpha-synuclein-targeted therapeutics, reflecting the current state where symptomatic treatments (dopaminergic therapy for motor symptoms) remain the standard of care while disease-modifying approaches are still in development 5.