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.
Highlights
Prion diseases or transmissible spongiform encephalopathies are fatal spongiform neurodegenerative disorders in humans and in other mammals
Consequence of Prion Infection on Vesicular Trafficking While the above studies demonstrate that the transport and the localization of PrPc and PrPSc to specific sub-cellular compartments are critical for prion propagation, there is evidence that prion Inint.fJe.cMtiool.nScoi.r20t2h0e, 21p,r7e0s1e6nce of PrPSc aggregates in intracellular vesicles negatively impact and6 oaflt1e9r endocytic vesicle trafficking. 44.1.1..RRaabbGGTTPPaasseess——CCoooorrddiinnaattoorrssooffVVeessicicuulalarrTTraraffiffcikcikningg
The impaired lysosomal acidification and reduction in the efficiency of lysosomal degradation as reflected by the increased half-life of epidermal growth factor receptor (EGFR) upon prion infection can be linked to the reduced membrane associated Rab7 [85]. These findings further indicate a potential loss of other Rab7 functions, as well in prion-infected neurons (Figure 4). Another vesicular trafficking pathway affected by prion infection is the retrograde trafficking as observed from the analysis of RNA expression profiles in sporadic CJD brains implicating down regulated gene expression, as well as reduced protein levels of vacuolar protein sorting-associated protein 35 (Vps 35), a subunit of the retromer complex [86]
Summary
Prion diseases or transmissible spongiform encephalopathies are fatal spongiform neurodegenerative disorders in humans and in other mammals. The classic hallmark of prion diseases is the deposition of amyloid plaques in the brain, which leads to progressive neuronal loss, spongiosis, and astrogliosis [1,2]. They are caused by prions, proteinaceous infectious particles arising upon misfolding of the ubiquitously expressed cellular protein named PrPc into an insoluble and aggregation-prone conformer named PrPSc [3,4]. Prion diseases in humans can have three different etiologies—sporadic, familial or acquired by infection [5,6]. The zoonotic potential of prion diseases was manifested through the transmission of BSE to humans, giving rise to a novel form of human prion disease called vCJD, in the 1990s, mostly in the UK, claiming more than 200 lives [14,15]
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