What is alpha synuclein?

Alpha-Synuclein: Structure, Function, and Pathological Implications

Alpha-synuclein is a neuronal protein that plays a critical role in neurodegenerative diseases, particularly serving as the primary component of Lewy bodies in Parkinson's disease and related synucleinopathies, with its abnormal aggregation leading to neurodegeneration and cognitive decline. 1

Structure and Normal Function

• Alpha-synuclein is a 140 amino acid protein primarily expressed at presynaptic terminals in the central nervous system 2
• It exists physiologically in both soluble (unstructured) and membrane-bound (alpha-helical conformation) states, with its function requiring translocation between these states 3
• Alpha-synuclein is involved in synaptic function and vesicle trafficking, with evidence suggesting it regulates membrane stability and neuronal plasticity 2, 4
• The protein contains structural motifs at both N and C termini that are homologous to fatty acid-binding proteins, allowing it to bind fatty acids (with an apparent Kd of 12.5 μM for oleic acid) and potentially transport them between aqueous and membrane phospholipid compartments 5

Pathological Role in Neurodegenerative Diseases

• Alpha-synuclein is the predominant component of Lewy bodies, which are proteinaceous inclusions found in Parkinson's disease and cortical Lewy body dementia 3, 1
• Under pathogenic conditions, alpha-synuclein can misfold and aggregate to form oligomers and insoluble fibrils with increased beta-sheet configuration 6
• Current evidence suggests that oligomeric alpha-synuclein species, rather than insoluble aggregated forms, are associated with cytotoxicity 4
• Point mutations (A53T, A30P) and gene multiplications in the alpha-synuclein gene are linked to autosomal dominant forms of Parkinson's disease 4, 2

Classification of Lewy Body Disease

• Lewy body disease (LBD), including Parkinson's disease and dementia with Lewy bodies, is characterized by abnormal accumulation of alpha-synuclein within inclusions called Lewy bodies, as well as alpha-synuclein-immunoreactive neurites and diffuse cytoplasmic immunoreactivity 1
• LBD can be classified into five categories based on the distribution of alpha-synuclein pathology: none, brainstem-predominant, limbic (transitional), neocortical (diffuse), or amygdala-predominant 1
• Immunohistochemical detection of alpha-synuclein is the preferred method for identifying Lewy bodies, providing greater sensitivity than standard hematoxylin and eosin staining 1

Alpha-Synuclein in Different Neurodegenerative Disorders

• Parkinson's disease is a synucleinopathy with neuronal deposits of Lewy bodies predominantly composed of alpha-synuclein and ubiquitin 1
• In Parkinson's disease, Lewy body deposition initially involves the medulla oblongata, pontine tegmentum, and olfactory system, with later involvement of the substantia nigra and other deep gray nuclei, and finally deposition in the cortex 1
• Multiple System Atrophy (MSA) is also a synucleinopathy but differs from Parkinson's disease in that it features abnormal cytoplasmic inclusions of ubiquitin and alpha-synuclein in oligodendroglia 1, 7
• Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are tauopathies rather than synucleinopathies, with tau protein rather than alpha-synuclein accumulation 1, 7

Mechanisms of Neurodegeneration

• Alpha-synuclein can contribute to neurodegeneration through multiple mechanisms, including:
  • Direct formation of plasma membrane channels or modification of ion channel activity, altering membrane permeability 4
  • Abnormal association with mitochondria causing dysfunction (mitochondrial depolarization, calcium dysregulation, cytochrome c release) 4
  • Interference with autophagy regulation 4
• In dopaminergic neurons, alpha-synuclein dysfunction may promote a cycle involving elevation in cytoplasmic dopamine, oxidative stress, and disruption of vesicle function, ultimately leading to cell loss 2

Diagnostic Implications

• Immunohistochemical detection of alpha-synuclein is essential for the neuropathological assessment and classification of Lewy body diseases 1
• For accurate diagnosis, a tiered approach to assessment of Lewy body disease is recommended to reflect the typically ordered appearance of alpha-synuclein pathology in the brain 1
• "Neocortical LBD" is considered an adequate explanation for cognitive impairment or dementia, while "Brainstem-predominant LBD" in the setting of cognitive impairment should prompt consideration of other diseases 1