Infographic showing how neurodegenerative diseases have long been associated with aggregations of apparently toxic proteins
Infographic showing how neurodegenerative diseases have long been associated with aggregations of apparently toxic proteins

Infographic: Secret Lives of Neurodegeneration-Linked Proteins

Maligned peptides such as the Alzheimer’s-associated amyloid precursor protein may have critical roles in the healthy brain.

Catherine Offord
Catherine Offord

Catherine is a senior editor at The Scientist.

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Aug 1, 2022

ABOVE: adapted from: © istock.com, saemilee; © istock.com, ttsz; © istock.com, Dmitry Kovalchuk

Neurodegenerative diseases have long been associated with aggregations of apparently toxic proteins, whether that’s amyloid precursor protein (APP) in Alzheimer’s disease, α-synuclein in Parkinson’s, or huntingtin in Huntington’s. But when not mutated, misfolded, or otherwise misbehaving, these proteins seem to play critical roles in brain development and function, leading some researchers to suspect that the loss of those normal functions may play a role in disease. Some of the purported functions of three of these proteins, assessed primarily through in vitro and animal studies, are shown below.

Amyloid precursor protein’s roles outside of Alzheimer’s disease

Amyloid Precursor Protein

Amyloid-β, which is made when amyloid precursor protein (APP) breaks down, forms plaques in the brains of people with Alzheimer’s disease, and has long been viewed by researchers and pharmaceutical companies as the cause of neurodegeneration. But scientists are now digging into the the regular physiological roles of APP (a selection of which are highlighted below), and identifying ways in which the peptide may be important for normal brain function.

Neuralsignaling

Neural signaling

Binds to GABAB receptors on neurons, regulating the release of neurotransmitters such as GABA and glutamate
Intracellulartrafficking

Intracellular trafficking

Mediates the intracellular trafficking of vesicles and other materials
Neuronalgrowth

Neuronal growth

Promotes neurogenesis and may help direct neuronal migration during brain development
Wnt proteins

Other

Binds to Wnt proteins, influencing cell signaling and neuronal growth

Alpha-synuclein’s roles outside of Parkinson’s disease

Alpha-Synuclein

Alpha-synuclein misfolds and forms aggregations in the brains of people with Parkinson’s disease and related neurodegenerative disorders. While the protein has been better studied than some peptides involved in neurodegeneration, researchers are still discovering new physiological functions for it (a selection of which are highlighted below), some of which may be important in understanding its role in disease.

Neuralsignaling

Neural signaling

Regulates the release of neurotransmitters and other cargo from dopamine neurons
Intracellulartrafficking

Intracellular trafficking

Interacts with the membranes of vesicles and other cellular components, helping to regulate intracellular trafficking
DNArepair

DNA repair

Influences DNA repair pathways
Geneexpression

Gene expression

Influences gene expression by binding to and modulating the stability of messenger RNAs
Mitochondria

Other

Helps regulate mitochondrial and lysosomal homeostasis

Huntingtin’s roles outside of Huntington’s disease

Huntingtin

The causative mutation of Huntington’s, in the huntingtin gene, was identified in 1993. Much work since has focused on how the resulting mutant protein, which aggregates inside neurons and invades cell nuclei, contributing to the pathology of the disease. However, researchers are focusing more and more on the roles of the regular protein in healthy brain function (several of which are highlighted below) and on how better understanding these roles might shine a light on how the disease develops.

Intracellulartrafficking

Intracellular trafficking

Promotes the intracellular trafficking of vesicles and other materials
Neuronalgrowth

Neuronal growth

Regulates neuronal cell division and differentiation
DNArepair

DNA Repair

Influences DNA repair pathways
Geneexpression

Gene expression

Mediates transcription of dozens of genes
Apoptosis

Other

Protects neurons from programmed cell death (apoptosis)
adapted from: © istock.com, Dmitry Kovalchuk, ttsz

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This article was featured in August 2022, Issue 1 of the digest