The Role of Vesicle Trafficking Defects in the Pathogenesis of Prion and Prion-Like Disorders

Abstract

Prion diseases are fatal and transmissible neurodegenerative diseases in which the cellular form of the prion protein ‘PrPc’, misfolds into an infectious and aggregation prone isoform termed PrPSc, which is the primary component of prions. Many neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases, such as Huntington’s disease, are considered prion-like disorders because of the common characteristics in the propagation and spreading of misfolded proteins that they share with the prion diseases. Unlike prion diseases, these are non-infectious outside experimental settings. Many vesicular trafficking impairments, which are observed in prion and prion-like disorders, favor the accumulation of the pathogenic amyloid aggregates. In addition, many of the vesicular trafficking impairments that arise in these diseases, turn out to be further aggravating factors. This review offers an insight into the currently known vesicular trafficking defects in these neurodegenerative diseases and their implications on disease progression. These findings suggest that these impaired trafficking pathways may represent similar therapeutic targets in these classes of neurodegenerative disorders.

Loss of small GTPase Rab7 activation in prion infection negatively affects a feedback loop regulating neuronal cholesterol metabolism

“…A schematic representation of our study on how a loss in Rab7 activation can lead to elevated cholesterol levels is depicted in Figure 10 . Many neurodegenerative diseases present with similar impairments associated with vesicle trafficking and lysosomal maturation defects ( 36 ). In the case of prion infections, we have demonstrated that vesicular trafficking defects due to reduced Rab7 activation can result in elevated cholesterol levels.…”

“…The retrograde LDL trafficking to the Golgi complex is also affected, potentially due to a reduced interaction of Rab7 with Vps 35. Adapted from ( 36 ). …”

“…Active Rab proteins exist in the GTP bound form and are tethered by prenylation to vesicle membranes, where they exert their functions by interacting with the effector proteins. Guanine activating proteins catalyze the hydrolysis of GTP to GDP, rendering Rab-GDP, which is cytosolic and inactive ( 35 , 36 ).…”

Copper trafficking systems in cells: insights into coordination chemistry and toxicity

“…277 Given the prevalence of PrP c in lipid rafts at the plasma membrane, 278 Cu(II)-mediated PrP aggregates may also stimulate its endocytosis and vesicular trafficking at synapses, suggesting a potential role of PrP C in the uptake and efflux of Cu(II) under physiological conditions. 279,280…”

Prion Pathogenesis Revealed in a Series of the Special Issues “Prions and Prion Diseases”

“…It is thus conceivable that PrP Sc or mutant PrPs in neurons might target the intracellular vesicle trafficking system, eventually causing neuronal dysfunctions associated with prion diseases. In this series, Cherry and Gilch reviewed the possible mechanism of the PrP Sc -associated vesicular trafficking defect by highlighting how the Rab GTPase family-associated vesicular trafficking system is impaired in prion-infected neurons [ 17 ]. Alves et al also discussed the mechanism of the inter- and intra-cellular trafficking of PrP C and PrP Sc [ 18 ].…”