Emerging Roles of Exosomes in Huntington's Disease

Abstract

Huntington's disease (HD) is a rare hereditary autosomal dominant neurodegenerative disorder, which is caused by expression of mutant huntingtin protein (mHTT) with an abnormal number of glutamine repeats in its N terminus, and characterized by intracellular mHTT aggregates (inclusions) in the brain. Exosomes are small extracellular vesicles that are secreted generally by all cell types and can be isolated from almost all body fluids such as blood, urine, saliva, and cerebrospinal fluid. Exosomes may participate in the spreading of toxic misfolded proteins across the central nervous system in neurodegenerative diseases. In HD, such propagation of mHTT was observed both in vitro and in vivo. On the other hand, exosomes might carry molecules with neuroprotective effects. In addition, due to their capability to cross blood-brain barrier, exosomes hold great potential as sources of biomarkers available from periphery or carriers of therapeutics into the central nervous system. In this review, we discuss the emerging roles of exosomes in HD pathogenesis, diagnosis, and therapy.

Keywords: Huntington’s disease; biomarker; exosome; extracellular vesicle; huntingtin; neurodegeneration; polyQ; therapy.

Figure 1

Biosynthesis and composition of extracellular vesicles: (A) Exosomes originate from endosomal compartment, i.e., intraluminal vesicles of multivesicular bodies (MVB). On the other hand, microvesicles arise by outward budding of cytoplasmic membrane and apoptotic bodies are formed during programmed cell death; (B) Exosomes contain proteins, RNAs, lipids and small molecules of the source cell. Some of the molecules specifically incorporated during exosome biosynthesis can be used as markers for exosome detection (e.g., transmembrane tetraspanins CD9, CD63, CD81) or as a marker of neuronal origin (e.g., L1 cell adhesion molecule, L1CAM).

Figure 2

Overview of human huntingtin protein. Full-length HTT consists of 3144 amino acids, with a total molecular mass of 350 kDa. The N-terminal 17 amino acid region carries several post translational modification sites (such as acetylation, SUMOylation, phosphorylation, ubiquitination, etc.) and is followed by polyglutamine tract (polyQ; expanded in Huntington’s disease), proline rich region (PRR), HEAT repeat domains (H1-H4; the HEAT corresponds to proteins, where they were first described: huntingtin, elongation factor 3 [EF3], protein phosphatase 2A [PP2A], and the yeast kinase TOR). Leucine-rich nuclear export signal is located at the C-terminal region. The protein may undergo post translational modifications and/or protease cleavage on several sites, e.g., caspase-6 cleavage at aspartate 586 [50,72,75,76,77].

Figure 3

Formation of mHTT toxic species and cellular mechanisms to handle them. Mutant huntingtin protein carrying expanded polyglutamine sequence is prone to adopt abnormal conformation. Post translational modifications and protease cleavage may contribute to formation of misfolded N-terminal fragments. Molecular chaperones, such as Heat Shock Proteins, participate in re-folding of misfolded proteins. Once unsuccessful, the resulting misfolded proteins can be degraded by ubiquitin-proteasome system or autophagy. Accumulation of misfolded mHTT rich in β-sheet structure leads to aggregate formation, loss of neurons and Huntington’s disease symptoms. Misfolded proteins may be eliminated from neurons also by exosomal secretion [86,87,88].

Figure 4

Physiological roles of extracellular vesicles in the central nervous system. EVs released from neurons and glial cells show neurotrophic and neuroprotective effects, by regulation of synaptic transmission/plasticity, protection against stress and excitotoxicity and may support axon regeneration after injury. Astrocytes and microglia participate in removal of EVs produced by other cells and may contribute to degradation of unwanted proteins (including unfolded proteins) released through EVs [86,87,88,105,106,107].