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Abstract
The abnormal deposition of proteins in brain tissue is a common feature of neurodegenerative diseases (NDs) often accompanied by the spread of mutated proteins, causing neuronal toxicity. Exosomes play a fundamental role on their releasing in extracellular space after endosomal pathway activation, allowing to remove protein aggregates by lysosomal degradation or their inclusion into multivesicular bodies (MVBs), besides promoting cellular cross-talk. The emerging evidence of pathogenic mutations associated to ND susceptibility, leading to impairment of exosome production and secretion, opens a new perspective on the mechanisms involved in neurodegeneration. Recent findings suggest to investigate the genetic mechanisms regulating the different exosome functions in central nervous system (CNS), to understand their role in the pathogenesis of NDs, addressing the identification of diagnostic and pharmacological targets. This review aims to summarize the mechanisms underlying exosome biogenesis, their molecular composition and functions in CNS, with a specific focus on the recent findings invoking a defective exosome biogenesis as a common biological feature of the major NDs, caused by genetic alterations. Further definition of the consequences of specific genetic mutations on exosome biogenesis and release will improve diagnostic and pharmacological studies in NDs.
Highlights
A common pathological feature of many neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases is the abnormal deposition of proteins in the brain, with a role in neurodegeneration
Proteome studies have revealed that exosomes contain a conserved set of proteins across species, and the proteins commonly identified in exosomes include vesicle trafficking proteins, cell surface receptors, antigen presentation molecules, proteins involved in membrane fusion process, cell surface endosome-associated proteins and adhesion proteins
The fusion of multivesicular bodies (MVBs) with the plasma membrane leading to the extracellular release of exosomes is mediated by a number of proteins involved in membrane fusion, including soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), Rabs and other Ras GTPases tethering factors [52]
Summary
A common pathological feature of many neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases is the abnormal deposition of proteins in the brain, with a role in neurodegeneration. Exosomes containing normal Aβ levels and neuroprotective factors have a function of cleaner for synaptotoxic Aβ species, promoting neuroprotection [8] The impairment of this mechanism impacts on synapsis activity so that synaptic dysfunction is considered a hallmark in neurodegenerative disorders. Proteins associated with AD, PD and prion diseases, Creutzfeldt–Jakob-disease (CJD) or bovine spongiform encephalopathy (BSE) can be selectively incorporated into intraluminal vesicles of MVBs and released as exosomes into the extracellular environment Because they can be isolated from circulating fluids such as serum, urine, and CSF, they provide a potential source of biomarkers for neurological disorders [2]. We will discuss the emerging role of exosome functional impairment caused by specific pathogenic mutations in neurodegenerative diseases
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