Anti-Alpha-Synuclein

Anti-alpha-synuclein antibody therapy is attracting interest in both scientific and clinical communities due to findings in neurodegenerative research, particularly in animal studies.  

Pathogenic forms of the alpha-synuclein protein have been noted in the pathogenesis of certain neurodegenerative diseases called synucleinopathies.  

Synucleinopathies are a group of neurodegenerative disorders characterized by the abnormal accumulation of alpha-synuclein protein aggregates within nerve cells. These conditions include Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and other related disorders. 

The accumulation of alpha-synuclein aggregates leads to the progressive dysfunction and death of nerve cells, resulting in a range of motor and cognitive symptoms characteristic of synucleinopathies

In this article, we will explore the alpha-synuclein protein in the pathogenesis of neurodegenerative diseases, particularly Parkinson’s disease.  We will also explore the use of monoclonal antibody therapy targeting the alpha-synuclein protein in altering disease progression. 

We will begin with a discussion of the molecular structure and function of Anti-Alpha-Synuclein, examining its impact on neurological health, and discuss its potential as a biomarker in disease diagnosis and monitoring.

What is the Alpha-Synuclein Protein?

Definition and Molecular Structure of the Alpha-Synuclein Protein [7.]

Anti-Alpha-Synuclein refers to monoclonal antibodies that target alpha-synuclein, a protein primarily located in the brain. 

The SNCA gene produces a 140-amino acid protein known as α-synuclein which lacks a defined structure in water, making it "natively unfolded." However, it adopts α-helical structures when binding to negatively charged lipids like those in cellular membranes and β-sheet-rich structures over time. 

Structurally, it consists of three parts: an amino terminus with lipid-binding motifs for membrane interaction, a central hydrophobic region (NAC) responsible for β-sheet formation, and a negatively charged carboxyl terminus. Although shorter variants exist, their roles are less understood.

α-Synuclein belongs to a protein family primarily found in neurons, with its unique feature being the NAC region. It localizes to presynaptic terminals, though some variants may exhibit neuritic pathology. 

Notably, wild-type β-synuclein may offer neuroprotection but can become neurotoxic under certain conditions.  Its connection with pathological processes appears to stem from alterations in its structure, as it moves from a fluid, disorganized state to highly organized fibrils as seen in synucleinopathies.

Function of the Alpha-Synuclein Protein: What Does Alpha-Synuclein Do?  [7.]

The alpha-synuclein protein exerts its effects by altering and modulating neurotransmitter release.  It seems that in disease states, the aberrant functions of the alpha-synuclein protein are related to neurotransmitter release.  

α-Synuclein is abundant in the nervous system and is implicated in synaptic transmission modulation, possibly through its interactions with synaptic vesicles and proteins like CSP-α in the SNARE complex assembly, affecting neurotransmitter release regulation.

Studies on α-synuclein-deficient mice and cellular models with overexpressed α-synuclein have revealed alterations in neurotransmitter release, suggesting its role as a modulator. 

Its movements away from vesicles upon neuronal firing and subsequent return indicate involvement in vesicular biogenesis and synaptic pool organization. The chaperone-like function of α-synuclein may also influence SNARE complex assembly. 

It plays a key role in the smooth operation of neuronal communication, ensuring efficient signal transmission between nerve cells. Alpha-synuclein’s ability to bind to membranes and influence synaptic vesicles is essential for maintaining normal brain function.

Pathological Mechanisms in Neurodegenerative Disorders

In neurodegenerative disorders like Parkinson's disease, alpha-synuclein can misfold and form aggregates, leading to neuronal dysfunction and death through loss of neuronal membrane integrity and “neuron-to-neuron” disease spreading, as seen in prion diseases.  [8.]

The accumulation of these misfolded proteins results in the formation of Lewy bodies, a pathological hallmark of Parkinson’s disease. 

What is the Anti-Alpha-Synuclein Antibody?

The anti-alpha-synuclein antibody was developed in an attempt to slow or reverse the disease progression of several synucleinopathies, particularly Parkinson’s disease, the second most common neurodegenerative disease after Alzheimer’s.  [5.]

Anti-alpha-synuclein monoclonal antibody therapy involves the use of monoclonal antibodies specifically designed to target and neutralize alpha-synuclein protein aggregates in the brain. 

These antibodies are administered to individuals with synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), to potentially slow down or halt the progression of these neurodegenerative disorders. 

By binding to and clearing abnormal alpha-synuclein aggregates, this therapy aims to reduce neuronal toxicity and preserve brain function.

How Does Monoclonal Anti-Alpha-Synuclein Antibody Therapy Work?

Researchers are still elucidating the mechanism of action of this monoclonal antibody therapy, but current understanding presents two possible pathways: 

Clearance of Extracellular Alpha-Synuclein 

Antibodies assist in clearing extracellular alpha-synuclein aggregates by enhancing their uptake into microglia, specialized cells responsible for clearing debris in the brain. 

This process involves antibody-α-synuclein immune complexes entering microglia through specific receptors and being efficiently delivered to lysosomes for degradation. 

By reducing the accumulation of extracellular alpha-synuclein, antibody therapy slows down cell-to-cell transmission of the protein, thereby potentially slowing disease progression.

Physical Blocking of Extracellular Alpha-Synuclein

Antibodies can directly block the transfer of alpha-synuclein aggregates between cells. 

Studies have shown that certain antibodies physically interfere with the intercellular transmission of alpha-synuclein, preventing its spread in cell cultures and animal models. 

This mechanism suggests that antibodies may capture extracellular alpha-synuclein aggregates, hindering their transfer to neighboring cells and enhancing their clearance by microglia.

In summary, anti-alpha-synuclein monoclonal antibody therapy works by promoting the clearance of extracellular alpha-synuclein aggregates and physically blocking their transfer between cells, potentially slowing the progression of synucleinopathies.

Recent Research and Future Directions for Monoclonal Anti-Alpha-Synuclein Antibody Therapy

Two promising trials include the Phase 2 Trial of Anti-alpha-Synuclein Antibody in Early Parkinson’s Disease (PASADENA) and SPARK, which were recently published in the New England Journal of Medicine.  [4., 6.]

In these trials, two monoclonal antibodies, Prasenizumab and Cinpanemab, were explored.  Results for Cinpanemab showed no benefit with use over 52 weeks.  [4.]  Trials involving Prasenizumab were also disappointing.  [6.]

While pharmaceutical companies are turning their attention to other therapies to address synucleinopathies, believing that the presence of alpha-synuclein clumps may signal that the disease process is too far advanced, some hope remains for monoclonal antibody therapy in the treatment of diseases including Parkinson’s disease.  [3.]

Lab Testing for Anti-Alpha-Synuclein

The detection and measurement of the Alpha-Synuclein protein clumps is used to aid in early diagnosis and treatment for people at increased risk of developing synucleinopathies.  

Testing options include assessment of cerebrospinal fluid (CSF) and skin.  

Indications for Testing

Testing for Anti-Alpha-Synuclein is primarily indicated in the investigation of neurodegenerative disorders, such as Parkinson's disease and multiple system atrophy. It is relatively new but advancements are rapidly being made to attempt to identify and provide early treatment to individuals needing such measures.  [1., 2.]

Methodologies and Technologies

Testing the CSF for the presence of pathogenic, clumped alpha-synuclein proteins is called an alpha-synuclein seed amplification assay.  It’s currently only available as part of research trials.  [1.]

Additional testing options are being explored, including skin biopsy testing for phosphorylated alpha-synuclein proteins.  [2.]