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The connection between neurodegenerative diseases and template misfolding proteins


The links between Alzheimer’s, Parkinson’s, and Prion diseases

At first glance, neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and prion disease share many generalized features. While these are distinct clinical pathologies, they are all diseases of the central nervous system that usually impact the elderly. Initially, these all present with overlapping symptomology and are always fatal. Current treatments are limited to aiding in symptom management, but nothing yet exists to slow or halt the progression of disease.

These diseases share another, lesser known similarity: in each, clumps of protein can be found in the brain. These clumps, called aggregates, collect in the brain and central nervous system and interrupt normal activity, contributing to the disease state. Protein aggregates consist of host protein that would normally be found in the body, with one key difference: these proteins have undergone template misfolding.


What are template misfolding proteins?

To understand pathologically misfolding proteins, we first need to understand “healthy” proteins. In a healthy cell, proteins are produced and then folded to suit the job they are designed for. A misfolded protein is normally useless, and will get refolded or disposed of. However, in the case of these diseased proteins, the misfolded protein will provide a “template” for the conversion of new protein. When the two come into contact, the healthy protein will misfold to match the “template” provided. Over time, more and more of this misfolded protein will accumulate, creating aggregates that are deposited in the central nervous system. Protein aggregates are neurotoxic, causing neuronal injury or death and furthering disease progression.

The exact mechanism by which this misfolding occurs is unknown. In most cases it arises sporadically without a known cause; however, in some instances prion diseases can be inherited via genetic mutations or acquired through environmental exposure. Multiple types of proteins are known to undergo template misfolding, including Alpha-synuclein (α-syn), Amyloid Beta (Aβ), Tau, and PrP. Alpha-synuclein is associated with synucleinopathies such as Parkinson’s disease, Multiple System Atrophy and Dementia with Lewy Bodies, which are characterized largely by a decline in motor functions. Amyloid Beta and Tau are associated with Alzheimer’s, a disease affecting cognitive function and memory. PrP is associated with prion diseases, a group of spongiform encephalopathies, which affect multiple mammalian species and are rare in humans.


What is on the horizon

Currently, neurodegenerative disorders involving template misfolding proteins are invariably fatal. However, their common denominator, the misfolded protein aggregates, have implications for drug discovery and design. A common strategy in therapeutic development focuses on the reduction of neurotoxic protein aggregates; however, while this could be useful in delaying disease progression, it likely would not reverse or cure the disease. Gain’s current therapeutic candidate, GT-02287, would depart from this norm by targeting the start of the disease cascade, potentially inhibiting the onset of disease. GT-02287 is currently in a Phase 1 clinical trial, and has the potential to combat synucleinopathies and Parkinson’s disease.






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