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 signalingBinds to GABAB receptors on neurons, regulating the release of neurotransmitters such as GABA and glutamate
Intracellular traffickingMediates the intracellular trafficking of vesicles and other materials
Neuronal growthPromotes neurogenesis and may help direct neuronal migration during brain development
OtherBinds 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 signalingRegulates the release of neurotransmitters and other cargo from dopamine neurons
Intracellular traffickingInteracts with the membranes of vesicles and other cellular components, helping to regulate intracellular trafficking
DNA repairInfluences DNA repair pathways
Gene expressionInfluences gene expression by binding to and modulating the stability of messenger RNAs
OtherHelps 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 traffickingPromotes the intracellular trafficking of vesicles and other materials
Neuronal growthRegulates neuronal cell division and differentiation
DNA RepairInfluences DNA repair pathways
Gene expressionMediates transcription of dozens of genes
OtherProtects neurons from programmed cell death (apoptosis)
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This article was featured in August 2022, Issue 1 of the digest