What is alpha synuclein?

Alpha-Synuclein: A Key Protein in Neurodegenerative Diseases

Alpha-synuclein is a neuronal protein that serves 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 small soluble protein (140 amino acids) primarily expressed at presynaptic terminals in the central nervous system 2
• Physiologically, it exists in both soluble and membrane-bound states, in unstructured and alpha-helical conformations, respectively 3
• Its normal function appears to involve regulating membrane stability and neuronal plasticity, requiring translocation between subcellular compartments 2

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 1, 3
• In Parkinson's disease, Lewy body deposition follows a specific progression pattern:
  • Initially involves the medulla oblongata, pontine tegmentum, and olfactory system
  • Later spreads to the substantia nigra and other deep gray nuclei
  • Finally deposits in the cortex 4
• Abnormal processing leads to pathological changes in binding properties and function 3
• Phosphorylated alpha-synuclein (particularly at Ser-129) is extensively found in disease states and is often targeted for mono- and diubiquitination in synucleinopathy brains 5

Diseases Associated with Alpha-Synuclein Pathology (Synucleinopathies)

• Parkinson's disease (PD) - the most common synucleinopathy 4
• Dementia with Lewy bodies (DLB) 1
• Multiple system atrophy (MSA) 6
• Other neurodegenerative disorders with alpha-synuclein pathology 7

Classification of Lewy Body Disease

• Based on distribution of alpha-synuclein pathology, Lewy body disease can be classified into five categories:
  1. None
  2. Brainstem-predominant
  3. Limbic (transitional)
  4. Neocortical (diffuse)
  5. Amygdala-predominant 4
• Neocortical Lewy body disease is considered an adequate explanation for cognitive impairment or dementia 4

Diagnostic Implications

• Immunohistochemical detection of alpha-synuclein is the preferred method for identifying Lewy bodies, providing greater sensitivity than standard hematoxylin and eosin staining 4, 1
• Alpha-synuclein pathology can be detected in cerebrospinal fluid using specialized assays 4
• In Alzheimer's disease assessment, alpha-synuclein pathology is evaluated as a potential co-morbid condition 4

Mechanisms of Toxicity

• Alpha-synuclein can induce neuronal toxicity through multiple pathways:
  • Aggregation into toxic oligomers and fibrils 7
  • Interaction with other proteins and molecules (synphilin-1, chaperone 14-3-3 protein, dopamine) 2
  • Prion-like spreading of misfolded protein throughout the brain 7, 6
  • Triggering neuroinflammation through microglial and astrocyte activation 7

Therapeutic Approaches Targeting Alpha-Synuclein

• Several therapeutic strategies are being developed:
  • Immunotherapy (passive or active) to remove aggregated alpha-synuclein 6
  • Small molecule anti-aggregants to modulate misfolding kinetics 6
  • Gene silencing approaches (antisense oligonucleotides, inhibitory RNA) 6
  • Pharmacological activation of alpha-synuclein degradation pathways 6
  • Novel delivery methods to improve brain penetration of therapeutics 6

Clinical Significance

• Alpha-synuclein dysfunction appears to be a common feature of all forms of Parkinson's disease 2
• The pattern and extent of alpha-synuclein pathology correlates with clinical symptoms in synucleinopathies 4, 1
• Alpha-synuclein biomarkers are increasingly important for diagnosis and monitoring of disease progression 4