Infographic: Secret Lives of Neurodegeneration-Linked Proteins

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-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.

	Neural signaling Binds to GABAB receptors on neurons, regulating the release of neurotransmitters such as GABA and glutamate
	Intracellular trafficking Mediates the intracellular trafficking of vesicles and other materials
	Neuronal growth Promotes neurogenesis and may help direct neuronal migration during brain development
	Other Binds to Wnt proteins, influencing cell signaling and neuronal growth

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

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.

	Neural signaling Regulates the release of neurotransmitters and other cargo from dopamine neurons
	Intracellular trafficking Interacts with the membranes of vesicles and other cellular components, helping to regulate intracellular trafficking
	DNA repair Influences DNA repair pathways
	Gene expression Influences gene expression by binding to and modulating the stability of messenger RNAs
	Other Helps regulate mitochondrial and lysosomal homeostasis

Huntingtin’s roles outside of Huntington’s disease

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.

	Intracellular trafficking Promotes the intracellular trafficking of vesicles and other materials
	Neuronal growth Regulates neuronal cell division and differentiation
	DNA Repair Influences DNA repair pathways
	Gene expression Mediates transcription of dozens of genes
	Other Protects neurons from programmed cell death (apoptosis)

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