Why immunotherapy might prevent neurodegeneration

The most common neurodegenerative disorders are associated with protein aggregates,¹ which appear to be pathologic rather than reactive,² said Professor Andrew Siderowf, Pennsylvania, USA.

The protein aggregates appear to be pathogenic and not reactive

Progression of the neurodegeneration results from spread of the misfolded proteins through the brain, which also spread throughout the body, he added. Monoclonal antibodies that target the proteins may therefore reduce aggregate load and slow clinical progression in neurodegenerative disease.³

Prion-like spread throughout the body

Mice injected with intracerebral α-synuclein develop α-synuclein aggregates far away from the injection sites,⁴ said Professor Siderowf.

Could spread begin in the enteric nervous system?

In humans, α-synuclein aggregates have been described in:

• salivary glands⁵
• colonic biopsies up to 5 years before a diagnosis of Parkinson's disease⁶
• healthy appendix⁷

The identification of α-synuclein pathology in these gastrointestinal-associated organs has led to the speculation that α-synuclein aggregates first develop in and then spread from the enteric nervous system.⁸

The spread of protein aggregates throughout the body has been compared to that of a prion—the proteins misfold into fibrils, propagate, and spread to adjacent neurons via dendrites and other neuronal connections,^1,9 explained Professor Siderowf.

Spread is neuronal rather than anatomic

Distinct strains of the protein aggregates can be demonstrated; and spread and disease development appear to depend on the strain.¹⁰

Predictable course of spread through the brain

The spread of the α-synuclein aggregates through the brain follows a predictable course in PD, added Professor Siderowf.

α-synuclein aggregation is first identified in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. It subsequently involves the brainstem, then the midbrain, and finally the neocortex.¹¹

Identification and targeting of protein aggregates

Identification and targeting of protein aggregates is an exciting prospect for future diagnostic methods and treatments for neurodegenerative disorders.

Antibodies could block cell to cell spread

Professor Siderowf highlighted that early studies have shown that two protein amplification assays—the Protein-Misfolding Cyclic Amplification (PMCA) and the Real-Time Quaking-Induced Conversion (RT-QuIC) assays—have high sensitivity and specificity for detecting misfolded protein aggregates.

They therefore have the potential to identify people likely to develop synucleinopathies,¹² said Professor Siderowf.

Given the significance of different aggregate strains, these biologic assays also have the potential to distinguish between PD and Parkinson’s-plus syndromes.¹³