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.

Role of Exosomes in Brain Diseases

“…Exosomes secreted by ADSCs are considered critical for relieving HD phenotypes, which up-regulate phosphorylated CREB, PGC-1, and expedite non-apoptotic protein levels (Lee et al, 2016), notably alleviating mHtt aggregation in R6/2 mouse neurons (Deng et al, 2019;Lee et al, 2021). Thus, exosomecarried mHTT propagation is thought to be a novel mechanism for HD pathology, providing a potential therapeutic target for alleviating this neurodegenerative disease (Ananbeh et al, 2021) (Figure 1F).…”

“…In recent years, exosomes have attracted considerable interest in the study of brain diseases, such as Alzheimer's disease, Parkinson's disease, stroke, and traumatic brain injury, due to their critical importance in the disease process and potential value for clinical application. The role and molecular mechanisms of exosomes carrying proteins related to the brain diseases [amyloid precursor protein (APP), α-synuclein (α-syn), mHtt, PrPsc] have been emphatically explored (Hartmann et al, 2017 ; Leblanc et al, 2017 ; Wang J. K. T. et al, 2017 ; Hill, 2019 ; Li B. et al, 2020 ; Pan et al, 2020 ; Perez-Gonzalez et al, 2020 ; Singh and Muqit, 2020 ; Tsunemi et al, 2020 , 2021 ; Ananbeh et al, 2021 ; Soares Martins et al, 2021a ). Notably, their ability to transport cargo is a key mechanism involved in the spread of disease.…”

Plant Polyphenols for Aging Health: Implication from Their Autophagy Modulating Properties in Age-Associated Diseases

“…Neurodegenerative diseases are a range of diseases of the brain, including Parkinson’s disease (PD) and Alzheimer’s disease, which result in neuron damage, brain atrophy, and consequently, the loss of cognitive or physical abilities. Several factors, including oxidative, endoplasmic stress, impairment in protein folding machinery, defects of damaged protein/organelle clearance mechanism, play key roles in the disease pathogenesis [ 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 ] and targeting these mechanisms alleviates the condition and offers neuroprotection.…”

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington’s Disease and Human Blood Plasma

“…On the other hand, incorporation of misfolded mHTT into EVs may be neuroprotective by reducing intracellular mHTT aggregates [ 54 , 55 ] through their elimination from cells [ 56 ]. Due to the ability to cross the BBB, EVs have a great potential in delivery of therapeutics into CNS [ 57 ].…”