No, Alpha-Synuclein and Tau Are Distinct Proteins
Alpha-synuclein and tau are two completely different proteins with distinct molecular structures, cellular locations, and pathological roles in neurodegenerative diseases. They are separate entities that happen to interact under certain pathological conditions but are fundamentally not the same protein 1, 2.
Fundamental Differences Between the Proteins
Molecular Identity and Normal Function
- Tau is a microtubule-associated protein expressed in neuronal and glial cells, primarily located in axons where it stabilizes microtubules 1.
- Alpha-synuclein is a synaptic protein that is enriched at presynaptic terminals and plays a role in synaptic vesicle function 1, 2.
Primary Disease Associations
- Tau aggregation forms neurofibrillary tangles, which are the hallmark of Alzheimer's disease and various frontotemporal dementia syndromes (collectively called "tauopathies") 1.
- Alpha-synuclein aggregation forms Lewy bodies, which are the defining feature of Parkinson's disease, dementia with Lewy bodies, and other synucleinopathies 2, 3.
Why the Confusion May Arise
Co-occurrence in Disease States
- Both proteins can be found together in the same patient, as there is significant overlap and co-occurrence of alpha-synuclein and tau pathologies across the spectrum of neurodegenerative diseases 3, 4.
- Alpha-synuclein-positive inclusions are sometimes described in tauopathies and vice versa, suggesting crosstalk between these proteinopathies 4.
Shared Pathological Characteristics
- Both are intrinsically disordered proteins prone to pathological misfolding and aggregation 3, 5.
- Both can form toxic oligomers and abnormal intracellular aggregates under pathological conditions 4.
- Both proteins can interact directly with each other in cells, and their pathological conformations can template further misfolding and aggregation of each other 3, 4, 6.
Similar Biomarker Behavior
- In certain conditions like Creutzfeldt-Jakob disease, both alpha-synuclein and tau are massively increased in CSF, possibly related to rapid neurodegeneration 1.
- Elevated CSF tau occurs in inflammatory and neoplastic CNS diseases, not just Alzheimer's disease, while alpha-synuclein elevation is seen in conditions beyond typical synucleinopathies 1.
Clinical Implications
Diagnostic Considerations
- CSF tau measurement (total tau or phosphorylated-tau) serves as a biomarker for neuronal injury in Alzheimer's disease and other conditions, with optimal cut-offs ranging from >1072 pg/mL to >1400 pg/mL depending on the assay 1.
- Alpha-synuclein detection via immunohistochemistry is the preferred method for identifying Lewy bodies in Parkinson's disease and related disorders, providing greater sensitivity than standard staining 2.
Important Caveat
- Neither protein is disease-specific when elevated; tau can be elevated in prion diseases and other conditions beyond Alzheimer's disease, while alpha-synuclein pathology extends beyond classic Parkinson's disease 1.
- The combination of low CSF Aβ42 with elevated CSF tau provides high likelihood of progression to Alzheimer's disease in patients with mild cognitive impairment, demonstrating that tau must be interpreted in context 1.